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Find video protocols related to scientific articles indexed in Pubmed.
Pulsed magnetic field accelerate proliferation and migration of cardiac microvascular endothelial cells.
Bioelectromagnetics
PUBLISHED: 07-17-2014
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Heart failure is a disease with multifactorial causes. Recently it was established that reduction in vascular density promoted the progression from adaptive cardiac hypertrophy to heart failure, therefore, therapeutic angiogenesis may be a promising method for treating heart failure. Cardiac microvascular endothelial cells (CMECs) play a major role in cardiac angiogenesis. In the present study, we investigated the direct and indirect effect of pulsed magnetic field (PMF) on the proliferation and migration of CMECs. CMECs were isolated from adult Sprague-Dawley (SD) rat hearts. We found PMF with a frequency of 15?Hz and an intensity of 1.8?mT accelerated the proliferation and migration of CMECs and cardiac myocytes (CMs). Moreover, CMECs treated with PMF released 1.5-fold higher vascular endothelial growth factor (VEGF) and 2-fold higher fibroblast growth factor-2 (FGF-2) when compared with PMF-free cells. In addition, CMs treated with PMF released twofold higher FGF-2 compared with PMF-free cells, but there was no change in VEGF levels. Those results suggested PMF has both a direct autocrine mitogenic and an indirect paracrine effect on CMECs proliferation and migration, and the effect of PMF on intercellular communication between CMECs and CMs was partially dependent on FGF-2, but independent on VEGF. Bioelectromagnetics. © 2014 Wiley Periodicals, Inc.
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AKAP150 mobilizes cPKC-dependent cardiac glucotoxicity.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 07-08-2014
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Activation of conventional PKCs (cPKC) is a key signaling that directs the cardiac toxicity of hyperglycemia. AKAP150, a scaffold protein of the A-kinase anchoring proteins (AKAPs) family, is less defined regarding its capability to anchor and regulate cardiac cPKC signaling. This study was designed to investigate the role of AKAP150 in cPKC-mediated cardiac glucotoxicity. In cardiac tissues from streptozotocin-induced diabetic rats and high-glucose-treated neonatal rat cardiomyocytes, both mRNA and protein levels of AKAP150 increased significantly, and marked elevations were observed in cPKC activity and both expression and phosphorylation levels of p65 NF-?B and p47(phox). AKAP150 knockdown was established via intramyocardial injection in vivo and transfection in vitro of adenovirus carrying AKAP150-targeted shRNA. Downregulation of AKAP150 reversed diabetes-induced diastolic dysfunction as manifested by decreased left ventricular end-diastolic diameter and early/late mitral diastolic wave ratio. AKAP150 inhibition also abrogated high-glucose-induced cardiomyocyte apoptosis (TUNEL staining and annexin V/propidium iodide flow cytometry) and oxidative stress (ROS production, NADPH oxidase activity, and lipid peroxidation). More importantly, reduced AKAP150 expression significantly inhibited high-glucose-induced membrane translocation and activation of cPKC and suppressed the increases in the phosphorylation of p65 NF-?B and p47(phox). Immunofluorescent coexpression and immunoprecipitation indicated enhanced anchoring of AKAP150 with cPKC within the plasma membrane under hyperglycemia, and AKAP150 preferentially colocalized and functionally bound with PKC? and -? isoforms. These results suggest that cardiac AKAP150 positively responds to hyperglycemia and enhances the efficiency of glucotoxicity signaling through a cPKC/p47(phox)/ROS pathway that induces myocardial dysfunction, cardiomyocyte apoptosis, and oxidative stress.
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Nine-month angiographic and two-year clinical follow-up of polymer-free sirolimus-eluting stent versus durable-polymer sirolimus-eluting stent for coronary artery disease: the Nano randomized trial.
Chin. Med. J.
PUBLISHED: 06-04-2014
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First generation drug-eluting stents (DES) were associated with a high incidence of late stent thrombosis (ST), mainly due to delayed healing and re-endothelization by the durable polymer coating. This study sought to assess the safety and efficacy of the Nano polymer-free sirolimus-eluting stent (SES) in the treatment of patients with de novo coronary artery lesions.
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Effective glycaemic control critically determines insulin cardioprotection against ischaemia/reperfusion injury in anaesthetized dogs.
Cardiovasc. Res.
PUBLISHED: 05-20-2014
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Experimental evidence has shown significant cardioprotective effects of insulin, whereas clinical trials produced mixed results without valid explanations. This study was designed to examine the effect of hyperglycaemia on insulin cardioprotective action in a preclinical large animal model of myocardial ischaemia/reperfusion (MI/R).
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Selective inhibition of inositol hexakisphosphate kinases (IP6Ks) enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction.
Basic Res. Cardiol.
PUBLISHED: 05-08-2014
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5-Diphosphoinositol pentakisphosphate (IP7), formed by a family of inositol hexakisphosphate kinases (IP6Ks), has been demonstrated to be a physiologic inhibitor of Akt. IP6K inhibition may increase Akt activation in mesenchymal stem cells (MSCs), resulting in enhanced cardiac protective effect after transplantation. The aim of this study was to investigate the role of IP6Ks for improving MSCs' functional survival and cardiac protective effect after transplantation into infarcted mice hearts. Bone marrow-derived mesenchymal stem cells, isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein positive (Fluc(+)-eGFP(+)) transgenic mice, were preconditioned with IP6Ks inhibitor TNP (0.5, 1, 5, and 10 ?mol/L) for 2 h followed by 6 h of hypoxia and serum deprivation (H/SD) injury. TNP concentration dependently significantly decreased IP7 production with increased Akt phosphorylation. Moreover, TNP at 10 ?mol/L significantly improved the viability and enhanced the paracrine effect of MSCs after H/SD. Furthermore, MSCs were transplanted into infarcted hearts with or without selective IP6Ks inhibition. Longitudinal in vivo bioluminescence imaging and immunofluorescent staining revealed that TNP pretreatment enhanced the survival of engrafted MSCs, which promoted the anti-apoptotic and pro-angiogenic efficacy of MSCs in vivo. Furthermore, MSC therapy with IP6Ks inhibition significantly decreased fibrosis and preserved heart function. This study demonstrates that inhibition of IP6Ks promotes MSCs engraftment and paracrine effect in infarcted hearts at least in part by down-regulating IP7 production and enhancing Akt activation, which might contribute to the preservation of myocardial function after MI.
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TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury.
Basic Res. Cardiol.
PUBLISHED: 05-07-2014
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NLRP3 inflammasome is necessary for initiating acute sterile inflammation. Recent studies have demonstrated that NLRP3 inflammasome is up-regulated and mediates myocardial ischemia/reperfusion (MI/R) injury. However, the signaling pathways that lead to the activation of NLRP3 inflammasome by MI/R injury have not been fully elucidated. C57BL/6J mice were subjected to 30 min ischemia and 3 or 24 h reperfusion. The ischemic heart exhibited enhanced inflammasome activation as evidenced by increased NLRP3 expression and caspase-1 activity and increased IL-1? and IL-18 production. Intramyocardial NLRP3 siRNA injection or an intraperitoneal injection of BAY 11-7028, an inflammasome inhibitor, attenuated macrophage and neutrophil infiltration and decreased MI/R injury, as measured by cardiomyocyte apoptosis and infarct size. The ischemic heart also exhibited enhanced interaction between Txnip and NLRP3, which has been shown to be a mechanism for activating NLRP3. Intramyocardial Txnip siRNA injection also decreased infarct size and NLRP3 activation. In vitro experiments revealed that NLRP3 was expressed in cardiac microvascular endothelial cells (CMECs), but was hardly expressed in cardiomyocytes. Simulated ischemia/reperfusion (SI/R) stimulated NLRP3 inflammasome activation in CMECs, but not in cardiomyocytes. Moreover, CMECs subjected to SI/R injury increased interactions between Txnip and NLRP3. Txnip siRNA diminished NLRP3 inflammasome activation and SI/R-induced injury, as measured by LDH release and caspase-3 activity in CMECs. ROS scavenger dissociated TXNIP from NLRP3 and inhibited the activation of NLRP3 inflammasome in the CMECs. For the first time, we demonstrated that TXNIP-mediated NLRP3 inflammasome activation in CMECs was a novel mechanism of MI/R injury. Interventions that block Txnip/NLRP3 signaling to inhibit the activation of NLRP3 inflammasomes may be novel therapies for mitigating MI/R injury.
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Adiponectin regulates SR Ca(2+) cycling following ischemia/reperfusion via sphingosine 1-phosphate-CaMKII signaling in mice.
J. Mol. Cell. Cardiol.
PUBLISHED: 04-15-2014
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The adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. Recent studies have demonstrated that APN induces a marked Ca(2+) influx in skeletal muscle. However, whether APN modulates [Ca(2+)]i activity, especially [Ca(2+)]i transients in cardiomyocytes, is still unknown. This study was designed to determine whether APN modulates [Ca(2+)]i transients in cardiomyocytes. Adult male wild-type (WT) and APN knockout (APN KO) mice were subjected to myocardial ischemia/reperfusion (I/R, 30min/30min) injury. CaMKII-PLB phosphorylation and SR Ca(2+)-ATPase (SERCA2) activity were downregulated in I/R hearts of WT mice and further decreased in those of APN KO mice. Both the globular domain of APN and full-length APN significantly reversed the decrease in CaMKII-PLB phosphorylation and SERCA2 activity in WT and APN KO mice. Interestingly, compared with WT littermates, single myocytes isolated from APN KO mice had remarkably decreased [Ca(2+)]i transients, cell shortening, and a prolonged Ca(2+) decay rate. Further examination revealed that APN enhances SERCA2 activity via CaMKII-PLB signaling. In in vivo and in vitro experiments, both APN receptor 1/2 and S1P were necessary for the APN-stimulated CaMKII-PLB-SERCA2 activation. In addition, S1P activated CaMKII-PLB signaling in neonatal cardiomyocytes in a dose dependent manner and improved [Ca(2+)]i transients in APN KO myocytes via the S1P receptor (S1PR1/3). Further in vivo experiments revealed that pharmacological inhibition of S1PR1/3 and SERCA2 siRNA suppressed APN-mediated cardioprotection during I/R. These data demonstrate that S1P is a novel regulator of SERCA2 that activates CaMKII-PLB signaling and mediates APN-induced cardioprotection.
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Acute insulin resistance mediated by advanced glycation endproducts in severely burned rats.
Crit. Care Med.
PUBLISHED: 03-28-2014
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Hyperglycemia often occurs in severe burns; however, the underlying mechanisms and importance of managing postburn hyperglycemia are not well recognized. This study was designed to investigate the dynamic changes of postburn hyperglycemia and the underlying mechanisms and to evaluate whether early glycemic control is beneficial in severe burns.
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A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type i diabetes-induced cardiac dysfunction: Role of AMPK-regulated autophagy.
Biochim. Biophys. Acta
PUBLISHED: 03-27-2014
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Mitochondrial aldehyde dehydrogenase (ALDH2) is known to offer myocardial protection against stress conditions including ischemia-reperfusion injury, alcoholism and diabetes mellitus although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on diabetes-induced myocardial injury with a focus on autophagy. Wild-type FVB and ALDH2 transgenic mice were challenged with streptozotozin (STZ, 200mg/kg, i.p.) for 3months to induce experimental diabetic cardiomyopathy. Diabetes triggered cardiac remodeling and contractile dysfunction as evidenced by cardiac hypertrophy, decreased cell shortening and prolonged relengthening duration, the effects of which were mitigated by ALDH2. Lectin staining displayed that diabetes promoted cardiac hypertrophy, the effect of which was alleviated by ALDH2. Western blot analysis revealed dampened autophagy protein markers including LC3B ratio and Atg7 along with upregulated p62 following experimental diabetes, the effect of which was reconciled by ALDH2. Phosphorylation level of AMPK was decreased and its downstream signaling molecule FOXO3a was upregulated in both diabetic cardiac tissue and in H9C2 cells with high glucose exposure. All these effect were partly abolished by ALDH2 overexpression and ALDH2 agonist Alda1. High glucose challenge dampened autophagy in H9C2 cells as evidenced by enhanced p62 levels and decreased levels of Atg7 and LC3B, the effect of which was alleviated by the ALDH2 activator Alda-1. High glucose-induced cell death and apoptosis were reversed by Alda-1. The autophagy inhibitor 3-MA and the AMPK inhibitor compound C mitigated Alda-1-offered beneficial effect whereas the autophagy inducer rapamycin mimicked or exacerbated high glucose-induced cell injury. Moreover, compound C nullified Alda-1-induced protection against STZ-induced changes in autophagy and function. Our results suggested that ALDH2 protects against diabetes-induced myocardial dysfunction possibly through an AMPK -dependent regulation of autophagy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
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Inositol pyrophosphates mediate the effects of aging on bone marrow mesenchymal stem cells by inhibiting Akt signaling.
Stem Cell Res Ther
PUBLISHED: 03-06-2014
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Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been proposed as an ideal autologous stem cell source for cell-based therapy for myocardial infarction (MI). However, decreased viability and impaired function of aged MSCs hampered the therapeutic efficacy of engrafted MSCs, and the underlying mechanisms remain unclarified. Here, we investigated the role of inositol phosphates 6 kinase (IP6Ks) inhibition on the therapeutic efficacy of BM-MSCs and its underlying mechanism.
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NADPH oxidase 4 promotes cardiac microvascular angiogenesis after hypoxia/reoxygenation in vitro.
Free Radic. Biol. Med.
PUBLISHED: 01-21-2014
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Microvascular endothelial cell dysfunction plays a key role in myocardial ischemia/reperfusion (I/R) injury, wherein reactive oxygen species (ROS)-dependent signaling is intensively involved. However, the roles of the various ROS sources remain unclear. This study sought to investigate the role of NADPH oxidase 4 (Nox4) in the cardiac microvascular endothelium in response to I/R injury. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and subjected to hypoxia/reoxygenation (H/R). Our results showed that Nox4 was highly expressed in CMECs, was significantly increased at both mRNA and protein levels after H/R injury, and contributed to H/R-stimulated increase in Nox activity and ROS generation. Downregulation of Nox4 by small interfering RNA transfection did not affect cell viability or ROS production under normoxia, but exacerbated H/R injury as evidenced by increased apoptosis and inhibited cell survival, migration, and angiogenesis after H/R. Nox4 inhibition also increased prolyl hydroxylase 2 (PHD2) expression and blocked H/R-induced increases in HIF-1? and VEGF expression. Pretreatment with DMOG, a specific competitive PHD inhibitor, upregulated HIF-1? and VEGF expression and significantly reversed Nox4 knockdown-induced injury. However, Nox2 was scarcely expressed and played a minimal role in CMEC survival and angiogenesis after H/R, though a modest upregulation of Nox2 was observed. In conclusion, this study demonstrated a previously unrecognized protective role of Nox4, a ROS-generating enzyme and the major Nox isoform in CMECs, against H/R injury by inhibiting apoptosis and promoting migration and angiogenesis via a PHD2-dependent upregulation of HIF-1/VEGF proangiogenic signaling.
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The key features of percutaneous coronary intervention with chronic total obstruction lesion of right coronary artery.
Ther Adv Cardiovasc Dis
PUBLISHED: 01-17-2014
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We summarize recent research on percutaneous coronary intervention of chronic total occlusion of the right coronary artery. We then explain the method and technology of forward and backward revascularization in chronic total occlusion of the right coronary artery. Finally, we emphasize the monitoring methods and key treating measures for better prognosis of the patients.
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Lin28a Protects against Hypoxia/Reoxygenation Induced Cardiomyocytes Apoptosis by Alleviating Mitochondrial Dysfunction under High Glucose/High Fat Conditions.
PLoS ONE
PUBLISHED: 01-01-2014
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The aim of the present study was to investigate the role of Lin28a in protecting against hypoxia/reoxygenation (H/R)-induced cardiomyocytes apoptosis under high glucose/high fat (HG/HF) conditions.
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Myocardial protective effect of extracellular superoxide dismutase gene modified bone marrow mesenchymal stromal cells on infarcted mice hearts.
Theranostics
PUBLISHED: 01-01-2014
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Extracellular superoxide dismutase (ecSOD) is a unique scavenger of superoxide anions and a promising target of gene therapy for ischemia/reperfusion injury (I/R). However, conventional gene therapies have limitation in effectiveness and efficiency. This study aimed to investigate the protective effects of ecSOD gene modified bone marrow mesenchymal stromal cells (BMSCs) on cardiac function improvement in mice infarcted heart.
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Baicalin protects the cardiomyocytes from ER stress-induced apoptosis: inhibition of CHOP through induction of endothelial nitric oxide synthase.
PLoS ONE
PUBLISHED: 01-01-2014
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Baicalin, the main active ingredient of the Scutellaria root, exerts anti-oxidant and anti-apoptotic effects in cardiovascular diseases. However, the therapeutic mechanism of baicalin remains unknown. Cultured neonatal rat cardiomyocytes were pre-treated with baicalin (0-50 µM) for 24 h, and subsequently treated with tunicamycin (100 ng/ml). Cell viability was detected by MTT assay, and cell damage was determined by LDH release and TUNEL assay. The expression of CHOP, JNK, caspase-3, eNOS was analyzed by western blot. NO was measured by DAF-FM staining. As a result, treatment with baicalin significantly reduced apoptosis induced by ER stress inducer tunicamycin in cardiomyocytes. Molecularly, baicalin ameliorated tunicamycin-induced ER stress by downregulation of CHOP. In addition, baicalin inverted tunicamycin-induced decreases of eNOS mRNA and protein levels, phospho eNOS and NO production through CHOP pathway. However, the protective effects of baicalin were significantly decreased in cardiomyocytes treated with L-NAME, which suppressed activation of nitric oxide synthase. In conclusion, our results implicate that baicalin could protect cardiomyocytes from ER stress-induced apoptosis via CHOP/eNOS/NO pathway, and suggest the therapeutic values of baicalin against ER stress-associated cardiomyocyte apoptosis.
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Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia-reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor.
Cardiovasc. Res.
PUBLISHED: 06-13-2013
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Apelin, an endogenous cytokine, has a number of biological effects on the cardiovascular system, including a cardioprotective effect and calcium modulation. Because the intracellular calcium abnormality is considered to play an important role in cardiac dysfunction induced by ischaemia-reperfusion (I/R), the aim of this study was to examine the effects of apelin-13 on I/R-induced changes in cardiac performance and sarcoplasmic reticulum (SR) function.
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NDRG2: a newly identified mediator of insulin cardioprotection against myocardial ischemia-reperfusion injury.
Basic Res. Cardiol.
PUBLISHED: 02-10-2013
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The N-myc downstream-regulated gene 2 (NDRG2) is involved in cell apoptosis and survival. Although reported to be highly expressed in the cardiac tissue, the biological function of NDRG2 in the heart remains to be established. Insulin exerts protective effects against myocardial ischemia/reperfusion (I/R) injury through the PI3K/Akt pathway. Here, we examined the changes in phosphorylation of NDRG2, a novel substrate and phosphoprotein of Akt, in insulin-induced protection against myocardial I/R. Rat hearts were subjected to 30 min regional ischemia followed by reperfusion with or without insulin at the onset of reperfusion. Reperfusion with insulin inhibited myocardial apoptosis and reduced infarct size, as well as significantly up-regulated myocardial Akt and NDRG2 phosphorylation levels compared with the I/R group. These effects of insulin were blocked by pretreatment with the PI3K inhibitor wortmannin or Akt inhibitor. To further ascertain the role of NDRG2 in insulin-induced cardioprotection, cardiomyocytes were transduced with a lentivirus encoding shRNA targeting NDRG2 (loss-of-function), which rendered the cells more susceptible to I/R injury and significantly blunted the anti-apoptotic effect of insulin. Moreover, the NDRG2 shRNA lentivirus was tested in vivo, and NDRG2 knockdown aggravated myocardial I/R injury and attenuated the insulin-mediated cardioprotection against I/R injury. Taken together, these results suggest a novel role of PI3K/Akt/NDRG2 signaling in the cardioprotective effect of insulin.
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Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism.
Diabetes
PUBLISHED: 01-30-2013
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Impaired cardiac microvascular function contributes to cardiovascular complications in diabetes. Glucagon-like peptide-1 (GLP-1) exhibits potential cardioprotective properties in addition to its glucose-lowering effect. This study was designed to evaluate the impact of GLP-1 on cardiac microvascular injury in diabetes and the underlying mechanism involved. Experimental diabetes was induced using streptozotocin in rats. Cohorts of diabetic rats received a 12-week treatment of vildagliptin (dipeptidyl peptidase-4 inhibitor) or exenatide (GLP-1 analog). Experimental diabetes attenuated cardiac function, glucose uptake, and microvascular barrier function, which were significantly improved by vildagliptin or exenatide treatment. Cardiac microvascular endothelial cells (CMECs) were isolated and cultured in normal or high glucose medium with or without GLP-1. GLP-1 decreased high-glucose-induced reactive oxygen species production and apoptotic index, as well as the levels of NADPH oxidase such as p47(phox) and gp91(phox). Furthermore, cAMP/PKA (cAMP-dependent protein kinase activity) was increased and Rho-expression was decreased in high-glucose-induced CMECs after GLP-1 treatment. In conclusion, GLP-1 could protect the cardiac microvessels against oxidative stress, apoptosis, and the resultant microvascular barrier dysfunction in diabetes, which may contribute to the improvement of cardiac function and cardiac glucose metabolism in diabetes. The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-mediated pathway.
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Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways.
Basic Res. Cardiol.
PUBLISHED: 01-24-2013
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The poor viability of transplanted stem cells hampers their therapeutic efficacy for treatment of myocardial infarction. The aim of this study was to investigate whether rosuvastatin improved survival of adipose-derived mesenchymal stem cells (AD-MSCs) after transplantation into infarcted hearts. AD-MSCs isolated from Tg(Fluc-egfp) mice which constitutively express both firefly luciferase (Fluc) and enhanced green fluorescent protein were transplanted into infarcted hearts with or without rosuvastatin administration. Longitudinal in vivo bioluminescence imaging and histological staining revealed that rosuvastatin enhanced the survival of engrafted AD-MSCs. Furthermore, combined therapy of AD-MSC and rosuvastatin reduced fibrosis, decreased cardiomyocyte apoptosis, and preserved heart function. AD-MSCs were then subjected to hypoxia and serum deprivation injury in vitro to mimic the ischemic environment. Rosuvastatin (10(-6) mmol/L) enhanced the viability and paracrine effect of AD-MSCs, and decreased their apoptotic rate. Western blotting revealed that rosuvastatin supplementation increased Akt and ERK phosphorylation, which resulted in FoxO3a phosphorylation and nuclear export. In addition, rosuvastatin administration decreased the pro-apoptotic proteins Bim and Bax, and increased the anti-apoptotic proteins Bcl-xL and Bcl-2. Furthermore, these effects were abolished by PI3K inhibitor LY294002 and MEK1/2 inhibitor U0126. This study demonstrates that rosuvastatin may improve the survival of engrafted AD-MSCs at least in part through the PI3K/Akt and MEK/ERK1/2 signaling pathways. Combination therapy with rosuvastatin and AD-MSCs has a synergetic effect on improving myocardial function after infarction.
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Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1? signaling contributing to increased vulnerability in diabetic heart.
Basic Res. Cardiol.
PUBLISHED: 01-09-2013
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Impaired mitochondrial biogenesis causes skeletal muscle damage in diabetes. However, whether and how mitochondrial biogenesis is impaired in the diabetic heart remains largely unknown. Whether adiponectin (APN), a potent cardioprotective molecule, regulates cardiac mitochondrial function has also not been previously investigated. In this study, electron microscopy revealed significant mitochondrial disorders in ob/ob cardiomyocytes, including mitochondrial swelling and cristae disorientation and breakage. Moreover, mitochondrial biogenesis of ob/ob cardiomyocytes is significantly impaired, as evidenced by reduced Ppargc-1a/Nrf-1/Tfam mRNA levels, mitochondrial DNA content, ATP content, citrate synthase activity, complexes I/III/V activity, AMPK phosphorylation, and increased PGC-1? acetylation. Since APN is an upstream activator of AMPK and APN plasma levels are significantly reduced in ob/ob mice, we further tested the hypothesis that reduced APN in ob/ob mice is causatively related to mitochondrial biogenesis impairment. One week of APN treatment of ob/ob mice activated AMPK, reduced PGC-1? acetylation, increased mitochondrial biogenesis, and attenuated mitochondrial disorders. In contrast, knocking out APN inhibited AMPK-PGC-1? signaling and impaired both mitochondrial biogenesis and function. The ob/ob mice exhibited lower survival rates and exacerbated myocardial injury after MI, when compared to controls. APN supplementation improved mitochondrial biogenesis and attenuated MI injury, an effect that was almost completely abrogated by the AMPK inhibitor compound C. In high glucose/high fat treated neonatal rat ventricular myocytes, siRNA-mediated knockdown of PGC-1? blocked gAd-enhanced mitochondrial biogenesis and function and attenuated protection against hypoxia/reoxygenation injury. In conclusion, hypoadiponectinemia impaired AMPK-PGC-1? signaling, resulting in dysfunctional mitochondrial biogenesis that constitutes a novel mechanism for rendering diabetic hearts more vulnerable to enhanced MI injury.
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AMPK-regulated and Akt-dependent enhancement of glucose uptake is essential in ischemic preconditioning-alleviated reperfusion injury.
PLoS ONE
PUBLISHED: 01-01-2013
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Ischemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury.
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Moderate dose insulin promotes function of endothelial progenitor cells.
Cell Biol. Int.
PUBLISHED: 06-11-2011
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EPCs (endothelial progenitor cells) regenerate the vascular endothelial cells and keep the integrity of the vascular endothelium and thus may retard the onset of atherosclerosis. Steady state levels of EPCs in the circulation were found to be correlated with cardiovascular event risks. Given the close relationship between insulin and the cardiovascular system, we tested the long-term effects of moderate-dose insulin treatment on bone marrow-derived EPCs. Rat bone marrow EPCs were exposed to various levels of insulin under normal (5 mmol/l) or high (40 mmol/l) glucose conditions for 7 days. Insulin at levels near the physiological range (0.1, 1 nmol/l) up-regulated EPCs proliferation, stimulated NO (nitric oxide) production and reduced EPC senescence and ROS (reactive oxygen species) generation under both normal- and high-glucose conditions. Glucose exerted deleterious effects on EPCs contrary to insulin. Western blot analysis suggested concomitant decrease of Akt phosphorylation and eNOS (endothelial nitric oxide synthase) expression by high-glucose treatment and increase with insulin administration. Thus, insulin promoted several activities of EPCs, which suggested a potential endothelial protective role of insulin. Akt/eNOS pathway may be involved in the modulation of EPCs function by glucose and insulin.
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Dynamic alteration of adiponectin/adiponectin receptor expression and its impact on myocardial ischemia/reperfusion in type 1 diabetic mice.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 05-17-2011
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The present study determined the dynamic change of adiponectin (APN, a cardioprotective adipokine), its receptor expression, and their impact upon myocardial ischemia/reperfusion (MI/R) injury during type 1 diabetes mellitus (T1DM) progression, and involved underlying mechanisms. Diabetic state was induced in mice via multiple intraperitoneal injections of low-dose streptozotocin. The dynamic change of plasma APN concentration and cardiac APN receptor-1 and -2 (AdipoR1/2) expression were assessed immediately after diabetes onset (0 wk) and 1, 3, 5, and 7 wk thereafter. Indicators of MI/R injury (infarct size, apoptosis, and LDH release) were determined at 0, 1, and 7 wk of DM duration. The effect of APN on MI/R injury was determined in mice subjected to different diabetic durations. Plasma APN levels (total and HMW form) increased, whereas cardiac AdipoR1 expression decreased early after T1DM onset. With T1DM progression, APN levels were reduced and cardiac AdipoR1 expression increased. MI/R injury was exacerbated with T1DM progression in a time-dependent manner. Administration of globular APN (gAD) failed to attenuate MI/R injury in 1-wk T1DM mice, while an AMP-activated protein kinase (AMPK) activator (AICAR) reduced MI/R injury. However, administration of gAD (and AICAR) reduced infarct size and cardiomyocyte apoptosis in 7-wk T1DM mice. In conclusion, our results demonstrate a dynamic dysfunction of APN/AdipoR1 during T1DM progression. Reduced cardiac AdipoR1 expression and APN concentration may be responsible for increased I/R injury susceptibility at early and late T1DM stages, respectively. Interventions bolstering AdipoR1 expression during early T1DM stages and APN supplementation during advanced T1DM stages may potentially reduce the myocardial ischemic injury in diabetic patients.
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Effects and mechanisms of ghrelin on cardiac microvascular endothelial cells in rats.
Cell Biol. Int.
PUBLISHED: 05-04-2011
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Ghrelin is thought to directly exert a protective effect on the cardiovascular system, specifically by promoting vascular endothelial cell function. Our study demonstrates the ability of ghrelin to promote rat CMEC (cardiac microvascular endothelial cell) proliferation, migration and NO (nitric oxide) secretion. CMECs were isolated from left ventricle of adult male Sprague-Dawley rat by enzyme digestion and maintained in endothelial cell medium. Dil-ac-LDL (1,1-dioctadecyl-3,3,3,3- tetramethylindocarbocyanine-labelled acetylated low-density lipoprotein) intake assays were used to identify CMECs. Cells were split into five groups and treated with varying concentrations of ghrelin as follows: one control non-treated group; three ghrelin dosage groups (1×10-9, 1×10-8, 1×10-7 mol/l) and one ghrelin+PI3K inhibitor group (1×10-7 mol/l ghrelin+20 ?mol/l LY294002). After 24 h treatment, cell proliferation capability was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and Western blot for PCNA (proliferating cell nuclear antigen) protein expression. Migration of CMECs was detected by transwell assays, and NO secretion of CMECs was measured via nitrate reduction. Protein expression of AKT and phosphorylated AKT in CMECs was measured by Western blot after exposure to various concentrations of ghrelin and the PI3K inhibitor LY294002. Our results indicate that ghrelin significantly enhanced cell growth at concentrations of 10-8 mol/l (0.271±0.041 compared with 0.199±0.021, P?=?0.03) and 10-7 mol/l (0.296±0.039 compared with 0.199±0.021, P<0.01). However, addition of the PI3K/AKT inhibitor LY294002 inhibited the ghrelin-mediated enhancement in cell proliferation (0.227±0.042 compared with 0.199±0.021, P?=?0.15). At a concentration between 10-8 and 10-7 mol/l, ghrelin caused a significant increase in the number of migrated cells compared with the control group (126±9 compared with 98±7, P?=?0.02; 142±6 compared with 98±7, P<0.01), whereas no such change could be observed in the presence of 20 ?mol/l of the PI3K/Akt inhibitor LY294002 (103±7 compared with 98±7, P?=?0.32). Ghrelin treatment significantly enhanced NO production in a dose-dependent fashion compared with the untreated control group [(39.93±2.12) ?mol/l compared with (30.27±2.71) ?mol/l, P?=?0.02; (56.80±1.98) ?mol/l compared with (30.27±2.71) ?mol/l, P<0.01]. However, pretreatment with 20 ?mol/l LY294002 inhibited the ghrelin-stimulated increase in NO secretion [(28.97±1.64) ?mol/l compared with (30.27±2.71) ?mol/l, P?=?0.37]. In summary, we have found that ghrelin treatment promotes the proliferation, migration and NO secretion of CMECs through activation of PI3K/AKT signalling pathway.
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Advanced glycation end products accelerate ischemia/reperfusion injury through receptor of advanced end product/nitrative thioredoxin inactivation in cardiac microvascular endothelial cells.
Antioxid. Redox Signal.
PUBLISHED: 04-26-2011
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The advanced glycation end products (AGEs) are associated with increased cardiac endothelial injury. However, no causative link has been established between increased AGEs and enhanced endothelial injury after ischemia/reperfusion. More importantly, the molecular mechanisms by which AGEs may increase endothelial injury remain unknown. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and incubated with AGE-modified bovine serum albumin (BSA) or BSA. After AGE-BSA or BSA preculture, CMECs were subjected to simulated ischemia (SI)/reperfusion (R). AGE-BSA increased SI/R injury as evidenced by enhanced lactate dehydrogenase release and caspase-3 activity. Moreover, AGE-BSA significantly increased SI/R-induced oxidative/nitrative stress in CMECs (as measured by increased inducible nitric oxide synthase expression, total nitric oxide production, superoxide generation, and peroxynitrite formation) and increased SI/R-induced nitrative inactivation of thioredoxin-1 (Trx-1), an essential cytoprotective molecule. Supplementation of EUK134 (peroxynitrite decomposition catalyst), human Trx-1, or soluble receptor of advanced end product (sRAGE) (a RAGE decoy) in AGE-BSA precultured cells attenuated SI/R-induced oxidative/nitrative stress, reduced SI/R-induced Trx-1 nitration, preserved Trx-1 activity, and reduced SI/R injury. Our results demonstrated that AGEs may increase SI/R-induced endothelial injury by increasing oxidative/nitrative injury and subsequent nitrative inactivation of Trx-1. Interventions blocking RAGE signaling or restoring Trx activity may be novel therapies to mitigate endothelial ischemia/reperfusion injury in the diabetic population.
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Downregulation of adiponectin induced by tumor necrosis factor ? is involved in the aggravation of posttraumatic myocardial ischemia/reperfusion injury.
Crit. Care Med.
PUBLISHED: 04-19-2011
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Recent clinical observations have indicated that nonlethal mechanical trauma significantly increases myocardial infarction risk even in the presence of completely normal coronary arteries. We investigated the molecular mechanisms responsible for exacerbation of ischemic myocardial injury after nonlethal mechanical trauma with a special focus on the role of tumor necrosis factor ? and its potential downstream effector adiponectin, a novel adipokine with anti-inflammatory and cardioprotective properties.
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Apelin stimulates glucose uptake through the PI3K/Akt pathway and improves insulin resistance in 3T3-L1 adipocytes.
Mol. Cell. Biochem.
PUBLISHED: 03-18-2011
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Apelin, a cytokine mainly secreted by adipocytes, is closely related with insulin resistance. The underlying molecular mechanisms of how apelin affects insulin resistance, however, are poorly understood. This study aimed to investigate the effect of apelin on glucose metabolism and insulin resistance in 3T3-L1 adipocytes. After 10 ng/ml TNF-? treatment for 24 h, insulin-stimulated glucose uptake was reduced by 47% in 3T3-L1 adipocytes. Apelin treatment improved glucose uptake in a time- and dose-dependent manner. Treatment of 1,000 nM apelin for 60 min maximally augmented glucose uptake in insulin-resistant 3T3-L1 adipocytes. Furthermore, apelin pre-incubation also increased adipocytes insulin-stimulated glucose uptake, and PI3K/Akt pathway were involved in these effects. In addition, immunocytochemistry staining and western blotting analysis indicated that apelin could increase glucose transporter 4 translocation from the cytoplasm to the plasma membrane. Apelin also increased the anti-inflammatory adipokine adiponectin mRNA expression while reducing that of pro-inflammatory adipokine interleukin-6 in insulin-resistant 3T3-L1 adipocytes. These results suggest that apelin stimulates glucose uptake through the PI3K/Akt pathway, promotes GLUT4 translocation from the cytoplasm to the plasma membrane, and modulates inflammatory responses in insulin-resistant 3T3-L1 adipocytes.
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Cardioprotective effects of tanshinone IIA pretreatment via kinin B2 receptor-Akt-GSK-3? dependent pathway in experimental diabetic cardiomyopathy.
Cardiovasc Diabetol
PUBLISHED: 01-13-2011
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Diabetic cardiomyopathy, characterized by myocardial structural and functional changes, is a specific cardiomyopathy develops in patients with diabetes mellitus. The present study was to investigate the role of kinin B2 receptor-Akt-glycogen synthase kinase (GSK)-3? signalling pathway in mediating the protective effects of tanshinone IIA (TSN) on diabetic cardiomyopathy.
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Variation of NDRG2 and c-Myc expression in rat heart during the acute stage of ischemia/reperfusion injury.
Histochem. Cell Biol.
PUBLISHED: 01-04-2011
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N-Myc downstream regulated gene 2 (NDRG2), a Myc-repressed gene, is highly expressed in heart tissue. NDRG2 increases in response to hypoxia-induced stress and is involved in hypoxia-induced radioresistance. However, little is known about the expression changes and possible roles of NDRG2 in the heart under hypoxia condition. Here, the authors show that NDRG2, mainly localized in cardiomyocyte cytoplasm, was significantly reduced in myocardial tissue after acute ischemia/reperfusion (I/R) injury. Meanwhile, c-Myc was up-regulated following acute I/R injury, and the expression of c-Myc was significantly inversely correlated with that of NDRG2. In addition, overexpression of c-Myc in primary cultured cardiomyocyte repressed NDRG2 expression. Furthermore, the increase of cardiomyocyte apoptosis was correlated with the decrease of NDRG2 protein during the acute phase of reperfusion. These data suggested for the first time that I/R injury-induced up-regulation of pro-apoptotic c-Myc expression may contribute to the down-regulation of anti-apoptotic NDRG2. This stress response might be involved in the novel mechanism of myocardial apoptosis induced by I/R injury in rat.
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Coronary vein angioplasty to facilitate implantation of left ventricular lead.
Europace
PUBLISHED: 09-06-2010
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Stenosis in the coronary veins can cause the failure of left ventricular (LV) lead implantation, which is the cornerstone of cardiac resynchronization therapy (CRT). There are several cases in which LV pacing could be possible after successful elimination of coronary vein stenosis by coronary vein angioplasty. The study was conducted to investigate the efficacy of coronary vein angioplasty with an aim to a facilitate implantation of LV lead.
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Toll-like receptor 4 signaling in dysfunction of cardiac microvascular endothelial cells under hypoxia/reoxygenation.
Inflamm. Res.
PUBLISHED: 06-28-2010
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This study was designed to detect the role of Toll-like receptor 4 (TLR4) signaling in the dysfunction of cardiac microvascular endothelial cells (CMECs) after hypoxia/reoxygenation (H/R).
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Association between serum levels of soluble CD40/CD40 ligand and organ damage in hypertensive patients.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 05-12-2010
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1. CD40 and CD40 ligand (CD40L) have a critical role in the pathophysiology and risk prediction of coronary artery syndrome, including atherothrombosis and atherosclerosis. However, the contribution of the CD40/CD40L dyad, especially the soluble form of CD40L (sCD40L), to the pathophysiology of hypertension and associated organ damage remains unknown. 2. In the present study, serum levels of CD40 and sCD40L were measured in 328 hypertensive patients with varying degrees of organ damage. The data revealed that serum levels of CD40 were significantly greater in patients with severe, but not mild, organ damage compared with patients without any organ damage. There were no significant differences in serum concentrations of sCD40L between patients with no, mild and severe organ damage. Concentrations of soluble CD40 were comparable in patients with mild organ damage that included left ventricular hypertrophy, retinal damage, renal dysfunction and proteinuria. In contrast, concentrations of soluble CD40 were increased significantly in patients with certain forms of severe organ damage, specifically stroke, but not coronary and peripheral artery disease. 3. Collectively, our data indicate that upregulation of the CD40 system in hypertensive patients with certain forms of severe end-organ damage may contribute to the pro-inflammatory, pro-atherogenic and prothrombotic milieu in hypertension.
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Nitrative inactivation of thioredoxin-1 increases vulnerability of diabetic hearts to ischemia/reperfusion injury.
J. Mol. Cell. Cardiol.
PUBLISHED: 04-15-2010
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Hyperglycemia (HG) significantly increases mortality after myocardial infarction (MI) in patients with and without established diabetes. The specific underlying mechanism remains unknown. The present study attempted to determine whether nitrative inactivation of thioredoxin-1 (Trx-1) may contribute to the exaggerated myocardial ischemia/reperfusion (I/R) injury observed in the hyperglycemic condition. Diabetes was induced by multiple intraperitoneal injections of low-dose streptozotocin (STZ) in mice. After 30 min ischemia by slip-knot ligature of the left anterior descending coronary artery, the myocardium was reperfused for 3h after knot release (for apoptosis, Trx-1-activity, and -nitration determination) or 24h (for cardiac function and infarct size determination). At 10 min before reperfusion, diabetic mice were randomized to receive vehicle, EUK134 (a peroxynitrite scavenger), recombinant human Trx-1 (rhTrx-1), or SIN-1 (a peroxynitrite donor) nitrated Trx-1 (N-Trx-1) administration. Diabetes intensified I/R-induced myocardial injury, evidenced by further enlarged infarct size, increased apoptosis, and decreased cardiac function in diabetic mice. Trx-1 nitrative inactivation was elevated in the diabetic heart before I/R and was further amplified after I/R. Treatment with EUK134 or rhTrx-1, but not N-Trx-1, before reperfusion significantly reduced Trx-1 nitration, preserved Trx-1 activity, attenuated apoptosis, reduced infarct size, and improved cardiac function in diabetic mice. Taken together, our results demonstrated that HG increased cardiac vulnerability to I/R injury by enhancing nitrative inactivation of Trx-1, suggesting that blockade of Trx-1 nitration, or supplementation of exogenous rhTrx-1, might represent novel therapies to attenuate cardiac injury after MI in diabetic patients.
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Pulsed magnetic field induces angiogenesis and improves cardiac function of surgically induced infarcted myocardium in Sprague-Dawley rats.
Cardiology
PUBLISHED: 02-04-2010
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OBJECTIVe: It was the aim of this study to investigate the impact of pulsed magnetic field (PMF) on ischemic myocardium, though it has been reported that PMF treatment is a safe and effective method to facilitate bone and cutaneous wound healing.
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A PKC-beta inhibitor treatment reverses cardiac microvascular barrier dysfunction in diabetic rats.
Microvasc. Res.
PUBLISHED: 01-05-2010
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The PKC-beta inhibitor ruboxistaurin (RBX or LY333531) prevents diabetic renal and retinal microvascular complications. However, the effect of RBX on diabetic cardiac microvascular dysfunction is still unclear. In this study, we aimed to investigate the effects and mechanisms of RBX treatment upon cardiac endothelial barrier dysfunction in high glucose states. We demonstrated RBX treatment suppressed high glucose induced PKC-betaII activation and phosphorylation of beta-catenin in vivo and in vitro experiments. Meanwhile, RBX treatment protected cardiac microvascular barrier function in diabetic animals and monolayer barrier function of cultured cardiac microvascular endothelial cells (CMECs), reproducing the same effect as PKC-betaII siRNA. These results provide new insight into protective properties of PKC-beta inhibitor against cardiac endothelial barrier dysfunction. PKC-beta inhibitor RBX prevented chronic cardiac microvascular barrier dysfunction and improved endothelial cell-cell junctional function in high glucose states.
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A PKC-beta inhibitor protects against cardiac microvascular ischemia reperfusion injury in diabetic rats.
Apoptosis
PUBLISHED: 01-02-2010
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PKC-beta inhibitor Ruboxistaurin (RBX or LY333531) can be used to reverse diabetic microvascular complication. However, it has not been previously established whether RBX can protect against ischemia/reperfusion (I/R) injury of cardiac microvessels in diabetic rats. STZ-induced diabetic rats were randomized into four groups and underwent I/R procedures. Cardiac barrier function and the region of cardiac microvascular lesion were examined. Cell monolayer barrier function was detected in cultured cardiac microvascular endothelial cells (CMECs) subjected to simulated I/R (SI/R). PKC-beta siRNA was transfected into CMECs to silence PKC-beta. Apoptosis Index of CMECs was detected by TUNEL assay and phosphor-LIMK2 protein expression was examined by Western blot analysis. RBX and insulin administration significantly reduced the cardiac microvascular lesion region and Apoptosis Index of endothelial cells (all P < 0.05 vs. no-treatment group). RBX decreased phosphor-LIMK2 expression (P < 0.05 vs. no-treatment group). RBX pretreatment and transfection with PKC-beta siRNA induced a rapid barrier enhancement in CMECs monolayer as detected by increased transendothelial electrical resistance (TER) and decreased FITC-dextran clearance (all P < 0.05 vs. no-treatment group). Meanwhile, RBX pretreatment and transfection with PKC-beta siRNA significantly decreased TUNEL positive CMECs and phosphor-LIMK2 expression in cultured CMECs (all P < 0.05 vs. no-treatment group). RBX pretreatment reduced F-actin/G-actin in cultured CMECs, reproducing the same effect as PKC-beta siRNA. These data indicate that PKC-beta inhibitor (RBX) may be helpful in attenuating the risk of severe cardiac microvascular I/R injury in diabetic rats partly due to its maintenance of endothelial barrier function and anti-apoptotic effect.
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Long-term myocardial functional improvement after autologous bone marrow mononuclear cells transplantation in patients with ST-segment elevation myocardial infarction: 4 years follow-up.
Eur. Heart J.
PUBLISHED: 06-09-2009
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To evaluate the safety profile and efficacy of bone marrow mononuclear cells (BMMNC) transplantation for ST-segment elevation myocardial infarction (STEMI) by assessing patients and their left ventricular function at up to 4 years follow-up.
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Insulin inhibits leukocyte-endothelium adherence via an Akt-NO-dependent mechanism in myocardial ischemia/reperfusion.
J. Mol. Cell. Cardiol.
PUBLISHED: 04-28-2009
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Clinical evidence indicates that intensive insulin therapy during critical illness protects the endothelium and contributes to prevention of organ failure and death but the mechanisms involved remain unclear. This study was designed to test the hypothesis that insulin inhibits adherence of polymorphonuclear leukocytes (PMNs) to endothelial cells in myocardial ischemia/reperfusion (MI/R) and to investigate the underlying mechanisms. Anesthetized rabbits were subjected to MI/R (45 min/4 h) and randomly received saline, glucose-insulin-potassium (GIK) or GK respectively (2 mL/kg/h, i.v.). In vitro study was performed on cultured endothelial cells subjected to simulated ischemia/reperfusion. In vivo treatment with GIK but not GK attenuated myocardial injury as evidenced by reduced plasma creatine kinase activity, myocardial apoptosis and infarct size in MI/R rabbits compared with the saline group. Interestingly, GIK but not GK significantly decreased coronary endothelial expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1), inhibited adherence of PMNs to coronary endothelium (107.7+/-7.4 vs. 155.0+/-9.2 PMNs/mm(2) in saline group, n=8, P<0.01), and therefore decreased myocardial PMNs accumulation. In cultured endothelial cells subjected to simulated ischemia/reperfusion, insulin (10(-)(7) M) increased Akt activity and eNOS phosphorylation with subsequent NO production, and concurrently exerted an anti-adhesive effect as manifested by reduced endothelial P-selectin and ICAM-1 surface expression and PMNs adherence (13.7+/-1.3% vs. 22.2+/-1.9% in vehicle, n=9, P<0.01), all of which are abolished by the specific Akt inhibitor. Furthermore, inhibition of insulin-stimulated NO production using either the selective eNOS inhibitor cavtratin or the NOS inhibitor L-NAME blocked the anti-adhesive effect of insulin. These results demonstrate that insulin reduces endothelial P-selectin and ICAM-1 expression, and thus inhibits leukocyte-endothelium adherence in MI/R rabbit hearts. The anti-adhesive property by insulin may be mediated by the Akt-mediated and NO-dependent pathway.
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Lipopolysaccharide up-regulates the expression of Fcalpha/mu receptor and promotes the binding of oxidized low-density lipoprotein and its IgM antibody complex to activated human macrophages.
Atherosclerosis
PUBLISHED: 04-16-2009
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Natural IgM antibodies against oxidized low-density lipoprotein (oxLDL) can inhibit the binding of oxLDL to macrophages and bacterial infection may deteriorate the pathogenesis of atherosclerosis. However, little is known about the molecular mechanisms underlying the action of bacterial lipopolysaccharide (LPS) in the binding of oxLDL to macrophages, contributing to the formation of foam macrophages. In this study, human monocytes-derived macrophages were cultured and incubated with purified human anti-oxLDL IgM antibodies (HAO-IgM), lipopolysaccharide (LPS) and oxLDL. The HAO-IgM were found specifically inhibited the binding of CuoxLDL to naïve macrophages but failed to inhibit the binding of CuoxLDL to LPS-activated macrophages and promoted the formation of CuoxLDL-mediated foam macrophages. Furthermore, the HAO-IgM F(ab)(2) or pre-incubation with unrelated IgM inhibited the binding of HAO-IgM/CuoxLDL complex to LPS-activated macrophages, suggesting that Fcalpha/mu receptor (Fcamr) may be responsible for the binding of HAO-IgM/CuoxLDL complex to LPS-activated macrophages. Indeed, LPS up-regulated the expression of Fcamr in macrophages in a dose- and time-dependent manner, which was diminished by treatment with anti-TLR4. In addition, LPS induced the phosphorylation of p38MAPK and translocation of NF-kappaB p65, contributing to the up-regulated expression of Fcamr in macrophages as treatment with specific inhibitor for p38MAPK (SB203580) or NF-kappaB (PDTC) attenuated the up-regulation of Fcalpha/mu receptor expression induced by LPS in macrophages. Inhibition of p38MAPK and NF-kappaB decreased the foam cells formation increased by Fcamr expression. These data demonstrated that LPS, through the TLR4 receptor, activated the p38MAPK and NF-kappaB pathways and up-regulate the expression of Fcamr in human macrophages, which promotes the binding of IgM/CuoxLDL complex to macrophages and the formation of foam cells. Therefore, our findings provide a new explanation why bacterial infection deteriorates the pathogenesis of atherosclerosis.
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High glucose sensitizes adult cardiomyocytes to ischaemia/reperfusion injury through nitrative thioredoxin inactivation.
Cardiovasc. Res.
PUBLISHED: 03-10-2009
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Ischaemic cardiac injury is significantly increased in diabetic patients, but its underlying mechanisms remain incompletely understood. The current study attempted to identify new molecular mechanisms potentially contributive to hyperglycaemic-exaggeration of myocardial ischaemic injury.
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Can insulin resistance be reversed by insulin therapy?
Med. Hypotheses
PUBLISHED: 02-26-2009
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Insulin resistance (IR) is a state of decreased tissue sensitivity to insulin, which commonly exists in patients with metabolic syndrome and diabetes, and leads to compensatory hyperinsulinemia to maintain normoglycemia. It is characterized by pathway-specific inhibition of the PI3K/Akt signaling, which concerns the positive actions of insulin including glucose and lipid metabolism, while other pathways including the Ras/MAPK pathway, which accounts for the negative actions of insulin such as stimulation of smooth muscle proliferation and secretion of endothelin-1, stay unaffected. Thus it was concerned that insulin therapy may exacerbate the negative effects of insulin in IR states. However, treatment of diabetes with insulin in clinical practice showed uniformly beneficial rather than harmful results. So we hypothesize that insulin therapy may itself reverse insulin resistance, thus avoiding magnification of the MAPK pathway-related deleterious effects. The mechanisms may include the recently revealed anti-inflammatory effects of insulin as well as its conventional glucose and free fatty acids lowering effects, and possibly may also include changes in body fat distribution and plasma adiponectin level. Whether there are direct mechanisms that insulin therapy modulates insulin sensitivity remains to be investigated.
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Involvement of activated astrocyte and microglia of locus coeruleus in cardiac pain processing after acute cardiac injury.
Neurol. Res.
PUBLISHED: 02-25-2009
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It is still not known whether the glial cell activation of locus coeruleus (LC) is involved in the neurophysiologic mechanism of the acute phase of heart disease. The aim of this study was to investigate whether the glial cell activation of LC responds to acute cardiac injury (ACI).
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Caveolin-1 restoration by cholesterol enhances the inhibitory effect of simvastatin on arginine vasopressin-induced cardiac fibroblasts proliferation.
Mol. Cell. Biochem.
PUBLISHED: 01-23-2009
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Caveolin-1 (cav1) has been implicated in the regulation of cell growth, and its expression can be regulated by cellular cholesterol content. In this study, we examined the effect of manipulating cellular cholesterol content on cav1 expression and the proliferation of adult rat cardiac fibroblasts (CFs) in the presence of arginine vasopressin (AVP). We found that AVP concentration-dependently down-regulated the expression of cav1 protein. Cav1 antisense treatment enhanced the proliferatory effect of AVP. Simvastatin, a HMG-CoA reductase inhibitor, further down-regulated cav1 protein, whereas repleting cells with cholesterol increased cav1 protein and enhanced the anti-growth effect of simvastatin. Our results provide a novel finding that cholesterol restoration may confer an additional inhibitory effect over simvastatin on AVP-induced CFs proliferation through cholesterol-cav1 interaction.
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Ischaemic post-conditioning protects both adult and aged Sprague-Dawley rat heart from ischaemia-reperfusion injury through the phosphatidylinositol 3-kinase-AKT and glycogen synthase kinase-3beta pathways.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 01-17-2009
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1. Numerous studies have demonstrated that ischaemic post-conditioning (IPoC) protects adult rats from myocardial ischaemia-reperfusion (I/R) injury. Recent evidence suggests compromised cardioprotection by IPoC in aged mice. The present study was designed to test the hypothesis that IPoC protects against I/R injury in aged hearts, potentially through a phosphatidylinositol 3-kinase (PI3-K)-Akt- and glycogen synthase kinase (GSK)-3beta-dependent mechanism. 2. Hearts from adult (3-4 months) or aged (16-18 months) Sprague-Dawley rats were subjected in vivo to 30 min ischaemia followed by 3 h reperfusion. Ischaemic post-conditioning (four cycles of 10 s reperfusion-10 s ischaemia) was applied at the beginning of reperfusion, either alone or in combination with the PI3-K inhibitor LY294002 (0.3 mg/kg). Infarct size and the phosphorylation of Akt and GSK-3beta were determined. 3. Ischaemic post-conditioning reduced infarct size in both adult and aged rat hearts. This protection was accompanied by a significant increase in phosphorylation of Akt and GSK-3beta. LY294002 abolished the IPoC-induced phosphorylation of Akt and GSK-3beta, as well as the infarct-limiting effect of IPoC in adult and aged rats. In addition, IPoC significantly attenuated plasma concentrations of creatine kinase and lactate dehydrogenase after reperfusion in both adult and aged rats. 4. In conclusion, IPoC, at the onset of reperfusion, reduces myocardial infarct size in both adult and aged rat hearts, potentially through a PI3-K-, Akt- and GSK-3beta-dependent mechanism.
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Nine-month angiographic and 2-year clinical follow-up of the NOYA biodegradable polymer sirolimus-eluting stent in the treatment of patients with de novo native coronary artery lesions: the NOYA I trial.
EuroIntervention
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This study sought to evaluate the safety and efficacy of the NOYA stent which is a cobalt chromium-based sirolimus-eluting stent (SES) with DL-polylactide biodegradable polymer (Medfavour Medical, Beijing, China) in treating de novo coronary artery lesions.
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PET of glucagonlike peptide receptor upregulation after myocardial ischemia or reperfusion injury.
J. Nucl. Med.
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Glucagonlike peptide (GLP-1) and its receptor (GLP-1R) exhibit cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in both animal studies and clinical trials. However, the kinetics of GLP-1R expression in the infarcted/ischemic myocardium has not yet been explored. The purpose of this study was to monitor the presence and time course of regional myocardial GLP-1R expression after MI/R with noninvasive PET.
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FTY720 protects cardiac microvessels of diabetes: a critical role of S1P1/3 in diabetic heart disease.
PLoS ONE
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Diabetes is associated with an increased risk of cardiac microvascular disease. The mechanisms by which this damage occurs are unknown. However, research suggests that signaling through the sphingosine-1-phosphates receptor 1 and 3 (S1P1/3) by FTY720, a sphiongolipid drug that is structually similar to SIP, may play a role in the treatment on cardiac microvascular dysfunction in diabetes. We hypothesized that FTY720 might exert the cardioprotective effects of S1P1 and S1P3 viaprotein kinase C-beta (PKC? II) signaling pathway.
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Multimodality imaging evaluation of functional and clinical benefits of percutaneous coronary intervention in patients with chronic total occlusion lesion.
Theranostics
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Aims: To determine the effects of percutaneous coronary intervention (PCI) on cardiac perfusion, cardiac function, and quality of life in patients with chronic total occlusion (CTO) lesion in left anterior descending (LAD) coronary artery.Methods and Results: Patients (n=99) with CTO lesion in the LAD coronary artery who had successfully undergone PCI were divided into three groups based on the SPECT/CTCA fusion imaging: (a) no severe cardiac perfusion defects (n=9); (b) reversible cardiac perfusion defects (n=40); or (c) fixed cardiac perfusion defects (n=50). No statistical difference of perfusion abnormality was observed at 6 months and 1 year after PCI in group (a). In group (b), SPECT/CTCA fusion imaging demonstrated that cardiac perfusion abnormality was significantly decreased 6 month and 1 year after PCI. Left ventricular ejection fraction (LVEF) increased significantly at 6 months and 1 year follow up. Quality of life improved at 6 months and 1 year after PCI procedure. Moreover, patients in group (c) also benefited from PCI therapy: a decrease in cardiac perfusion abnormality, an increase in LVEF, and an improvement in quality of life. PCI of coronary arteries in addition to LAD did not significantly affect cardiac function and quality of life improvement in each group.Conclusions: PCI exerts functional and clinical benefits in patients with CTO lesion in LAD coronary artery, particularly in patients with reversible cardiac perfusion defects. SPECT/CTCA fusion imaging may serve as a useful tool to evaluate the outcomes of patients with CTO lesion in LAD coronary artery.
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The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury.
Am. J. Physiol. Endocrinol. Metab.
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The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing roles in diabetic myocardial ischemia-reperfusion (MI/R) injury. We recently demonstrated nitrative modification of Trx leads to its inactivation and loss of cardioprotection. The present study is to determine the relationship between augmented RAGE expression and diminished Trx activity pertaining to exacerbated MI/R injury in the diabetic heart. The diabetic state was induced in mice by multiple intraperitoneal low-dose streptozotocin injections. RAGE small-interfering RNA (siRNA) or soluble RAGE (sRAGE, a RAGE decoy) was via intramyocardial and intraperitoneal injection before MI/R, respectively. Mice were subjected to 30 min of myocardial infarction followed by 3 or 24 h of reperfusion. At 10 min before reperfusion, diabetic mice were randomized to receive EUK134 (peroxynitrite scavenger), recombinant hTrx-1, nitrated Trx-1, apocynin (a NADPH oxidase inhibitor), or 1400W [an inducible nitric oxide synthase (iNOS) inhibitor] administration. The diabetic heart manifested increased RAGE expression and N(?)-(carboxymethyl)lysine (CML, major advanced glycation end product subtype) content, reduced Trx-1 activity, and increased Trx nitration after MI/R. RAGE siRNA or administration of sRAGE in diabetic mice decreased MI/R-induced iNOS and gp91(phox) expression, reduced Trx nitration, preserved Trx activity, and decreased infarct size. Apocynin or 1400W significantly decreased nitrotyrosine production and restored Trx activity. Conversely, administration of either EUK134 or reduced hTrx, but not nitrated hTrx, attenuated MI/R-induced superoxide production, RAGE expression, and CML content and decreased cardiomyocyte apoptosis in diabetic mice. Collectively, we demonstrate that RAGE modulates the MI/R injury in a Trx nitrative inactivation fashion. Conversely, nitrative modification of Trx blocked its inhibitory effect upon RAGE expression in the diabetic heart. This is the first direct evidence demonstrating the alternative cross talk between RAGE overexpression and nitrative Trx inactivation, suggesting that interventions interfering with their interaction may be novel means of mitigating diabetic MI/R injury.
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Low strength static magnetic field inhibits the proliferation, migration, and adhesion of human vascular smooth muscle cells in a restenosis model through mediating integrins ?1-FAK, Ca2+ signaling pathway.
Ann Biomed Eng
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The proliferation, migration, and adhesion of vascular smooth muscle cells (VSMCs) and their interactions with extracellular matrix are key features of atherosclerosis and restenosis. Recently, there has been evidence that magnetic fields exert multiple effects on the biological performance of cells and may aid in the treatment of vascular disease. However, the effect of a static magnetic field (SMF) on human VSMCs still remains unknown. In this study, we aimed to determine the effects of low strength SMF on human VSMCs in an in vitro restenosis model. A SMF was established using neodymium-yttrium-iron permanent magnet. Human umbilical artery smooth muscle cells (hUASMCs) were isolated and seeded to a fibronectin-coated plate to form an in vitro restenosis model and then exposed to a vertically oriented field of 5 militesla (mT). MTT, transwell, and adhesion assays were used to demonstrate that the proliferation, migration, and adhesion potential of hUASMCs were significantly decreased after exposure to 5 mT SMF for 48 h compared with a non-treated group. Meanwhile, confocal microscopy analysis was used to demonstrate that integrin ?(1) clustering was inhibited by exposure to 5 mT SMF. Furthermore, the phosphorylation of focal adhesion kinase (FAK) was markedly inhibited, and the upregulated cytosolic free calcium had been reversed (p < 0.05). However, the biological effects of low strength SMF on hUASMCs could be blocked by the administration of GRGDSP-the blockade of integrins. In conclusion, a low strength SMF can influence the proliferation, migration, and adhesion of VSMCs by inhibiting the clustering of integrin ?1, decreasing cytosolic free calcium concentration, and inactivating FAK. With further validation, SMFs may aid in attenuating abnormal VSMCs biological performance and has potential to block atherogenesis and prevent restenosis.
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S1P1 and S1P3 are potential markers of cardiac microangiopathy in diabetes.
Med. Hypotheses
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The prevalence of diabetes is rising rapidly throughout the world, accompanying with the increased occurrence of cardiovascular diseases in clinic. For now, the diagnosis of diabetic cardiovascular diseases has mainly based on the measurement of glucose levels in blood and cardiac function via electrocardiogram and ultrasound cardiogram. However, growing evidence strongly suggests that the assessment of Sphingosine-1-phosphate receptor 1/3 (S1P1/3) own advantages over present measurements in predicting the risk of developing diabetic cardiovascular diseases. This hypothesis may provide concept foundation for improving early diagnosis of cardiac microangiopathy in diabetes.
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Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3? and mitochondrial function.
BMC Med
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Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated.
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Changing strategies of the retrograde approach for chronic total occlusion during the past 7 years.
Catheter Cardiovasc Interv
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We reviewed the technical changes and results achieved with the retrograde approach since we introduced it 7 years ago.
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A conserved TGF?1/HuR feedback circuit regulates the fibrogenic response in fibroblasts.
Cell. Signal.
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Persistent fibroblast activation in wound repair is believed to be the key reason for fibrosis and transforming growth factor (TGF)? is considered as one of the key mediators for the fibrogenic response, with the detailed mechanism largely unknown. Here we found that TGF?1 treatment could induce a significant increase of endogenous TGF?1 expression by enhancing the mRNA stability in cardiac fibroblasts. Further study revealed that TGF?1 treatment translocated the nuclear HuR into cytoplasm, which in turn bound the ARE in the 3UTR of TGF?1 and increased the mRNA stability as seen from the RNA-IP and reporter assay. Knockdown of HuR decreased the endogenous expression of TGF?1 under exogenous TGF?1 treatment, simultaneously with the decrease of Col1a, Col3a and fibronectin expression. Our study here established a TGF?1/HuR feedback circuit regulating the fibrogenic response in fibroblasts, and targeting this feedback loop is of great potential to control fibrosis.
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Luteolin limits infarct size and improves cardiac function after myocardium ischemia/reperfusion injury in diabetic rats.
PLoS ONE
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The present study was to investigate the effects and mechanism of Luteolin on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in diabetic rats with myocardial ischemia/reperfusion (I/R) injury.
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Effect of autologous bone marrow mononuclear cells transplantation in diabetic patients with ST-segment elevation myocardial infarction.
Int. J. Cardiol.
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To investigate the efficacy and proposed mechanism of bone marrow mononuclear cells (BMMNCs) transplantation for diabetic and non-diabetic patients with ST-segment elevation myocardial infarction (STEMI).
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Effects of ghrelin on homocysteine-induced dysfunction and inflammatory response in rat cardiac microvascular endothelial cells.
Cell Biol. Int.
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Ghrelin is a well-characterized hormone that has protective effects on endothelial cells. Elevated HCY (homocysteine) can be a cardiovascular risk factor, but it is not known whether ghrelin can inhibit HCY-induced dysfunction and inflammatory response in rat CMECs (cardiac microvascular endothelial cells). We found that HCY treatment for 24 h inhibited proliferation and NO (nitric oxide) secretion, but with increased cell apoptosis and secretion of cytokines in CMECs. In contrast, ghrelin pretreatment significantly improved proliferation and NO secretion, and inhibited cell apoptosis and secretion of cytokines in HCY-induced CMECs. In addition, Western blot assay showed that NF-?B (nuclear factor ?B) and cleaved-caspase 3 expression were elevated, and PCNA (proliferating cell nuclear antigen) and eNOS (endothelial nitric oxide synthase) expression were decreased after treatment with HCY, which was significantly reversed by pretreatment with ghrelin. The data suggest that ghrelin inhibits HCY-induced CMEC dysfunction and inflammatory response, probably mediated by inhibition of NF-?B activation.
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The possible role of ribosomal protein S6 kinase 4 in the senescence of endothelial progenitor cells in diabetes mellitus.
Cardiovasc Diabetol
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The decrease and dysfunction of endothelial progenitor cells (EPCs) has been assumed as an important cause/consequence of diabetes mellitus (DM) and its complications, in which the senescence of EPCs induced by hyperglycemia may play an immensurable role. However, the mechanisms of EPCs senescence has not been fully investigated. Recently, ribosomal protein S6 kinase 4 (RSK4), a member of serine/threomine (Ser/Thr) kinase family and p53-related gene, is reported to regulate the replicative and stress-induced senescence of different cells.
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Simvastatin promotes cardiac microvascular endothelial cells proliferation, migration and survival by phosphorylation of p70 S6K and FoxO3a.
Cell Biol. Int.
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Restenosis severely limits the overall efficacy of interventions. One of the reasons is the lack of reendothelialization related to inhibition of endothelial cell proliferation and migration since drug is delivered to the luminal surface. Statins can promote angiogenic processes by improving endothelial function, proliferation and migration in cardiac microvascular endothelial cells (CMECs). This study clarified the effect of simvastatin on Akt/mTOR/p70 S6K and FoxO3a signaling pathways in rat CMECs following pretreated with rapamycin. Rapamycin treatment for 24?h inhibited CMECs proliferation, migration and NO (nitric oxide) secretion, but with increased cell apoptosis and reactive oxygen species (ROS) production. In contrast, simvastatin pretreatment significantly improved proliferation, migration and NO secretion, and inhibited CMECs apoptosis and ROS production in rapamycin-induced CMECs. Western blot assay showed that, after treatment with simvastatin, the phosphorylation of Akt/mTOR/p70 S6K and FoxO3a were up-regulatedin in rapamycin-induced CMECs, which was significantly reversed by pretreatment with LY294002. The data suggest that simvastatin inhibits rapamycin-induced CMECs dysfunction and apoptosis, probably through activation of PI3K/Akt/mTOR/p70 S6K and mTOR/FoxO3a signaling pathway in a sequential manner and this pathway may be important in some of the pleiotropic effects of statins.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.