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Find video protocols related to scientific articles indexed in Pubmed.
MicroRNA-451 Exacerbates Lipotoxicity in Cardiac Myocytes and High-Fat Diet-Induced Cardiac Hypertrophy in Mice through Suppression of the LKB1/AMPK Pathway.
Circ. Res.
PUBLISHED: 11-02-2014
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Rationale: In some type 2 diabetes patients without hypertension, cardiac hypertrophy and attenuated cardiac function are observed, and this insult is termed "diabetic cardiomyopathy." To date, microRNA functions in diabetic cardiomyopathy remain to be elucidated. Objective: To clarify the functions of microRNAs involved in diabetic cardiomyopathy caused by type 2 diabetes. Methods and Results: C57BL/6 mice were fed a high-fat diet (HFD) for 20 weeks, which induced obesity and type 2 diabetes. MicroRNA microarray analyses and real-time PCR revealed that miR-451 levels were significantly increased in the type 2 diabetes mouse hearts. Because excess supply of saturated fatty acids is a cause of diabetic cardiomyopathy, we stimulated neonatal rat cardiac myocytes (NRCMs) with palmitic acid and confirmed that miR-451 expression was increased in a dose- and time-dependent manner. Loss of miR-451 function ameliorated palmitate-induced lipotoxicity in NRCMs. Calcium-binding protein 39 (Cab39) is a scaffold protein of liver kinase B1 (LKB1), an upstream kinase of AMP-activated protein kinase (AMPK). Cab39 was a direct target of miR-451 in NRCMs and Cab39 overexpression rescued the lipotoxicity. To clarify miR-451 functions in vivo, we generated cardiomyocyte-specific miR-451 knockout (miR-451 cKO) mice. HFD-induced cardiac hypertrophy and contractile reserves were ameliorated in miR-451 cKO mice compared with control mice. Protein levels of Cab39 and phosphorylated AMPK were increased and phosphorylated mammalian target of rapamycin (mTOR) was reduced in miR-451 cKO mouse hearts compared with control mouse hearts. Conclusions: Our results demonstrate that miR-451 is involved in diabetic cardiomyopathy through suppression of the LKB1/AMPK pathway.
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Mitral annular morphology in mitral valve disease with three-dimensional transesophageal echocardiography.
J. Heart Valve Dis.
PUBLISHED: 08-01-2014
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Three-dimensional (3D) transesophageal echocardiography (TEE) is useful for the quantification of mitral valve structures. The study aim was to investigate, in quantitative manner, any differences in mitral valve anatomy among patients with mitral valve prolapse (MVP) or functional mitral regurgitation (FMR), compared to normal control subjects.
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AMAP1 as a negative-feedback regulator of nuclear factor-?B under inflammatory conditions.
Sci Rep
PUBLISHED: 05-07-2014
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NF-?B is a major transcriptional factor regulating many cellular functions including inflammation; therefore, its appropriate control is of high importance. The detailed mechanism of its activation has been well characterized, but that of negative regulation is poorly understood. In this study, we showed AMAP1, an Arf-GTPase activating protein, as a negative feedback regulator for NF-?B by binding with IKK?, an essential kinase in NF-?B signaling. Proteomics analysis identified AMAP1 as a binding protein with IKK?. Overexpression of AMAP1 suppressed NF-?B activity by interfering the binding of IKK? and NEMO, and deletion of AMAP1 augmented NF-?B activity. The activation of NF-?B induced translocation of AMAP1 to cytoplasm from cell membrane and nucleus, which resulted in augmented interaction of AMAP1 and IKK?. These results demonstrated a novel role of AMAP1 as a negative feedback regulator of NF-?B, and presented it as a possible target for anti-inflammatory treatments.
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MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo.
Sci Rep
PUBLISHED: 03-20-2014
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MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models.
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Relation of contrast-induced nephropathy to long-term mortality after percutaneous coronary intervention.
Am. J. Cardiol.
PUBLISHED: 02-24-2014
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There is little information on the effect of contrast-induced nephropathy (CIN) on long-term mortality after percutaneous coronary intervention in patients with or without chronic kidney disease (CKD). Of 4,371 patients who had paired serum creatinine (SCr) measurements before and after percutaneous coronary intervention and were discharged alive in the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry, the incidence of CIN (an increase in SCr of ?0.5 mg/dl from the baseline) was 5% in our study cohort. The rate of CIN in patients with CKD was 11%, although it was 2% without CKD (p <0.0001). During a median follow-up of 42.3 months after discharge, 374 patients (8.6%) died. After adjustment for prespecified confounders, CIN was significantly correlated with long-term mortality in the entire cohort (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.62 to 2.29, p <0.0001) and in patients with CKD (HR 2.62, 95% CI 1.91 to 3.57, p <0.0001) but not in patients without CKD (HR 1.23, 95% CI 0.47 to 2.62, p = 0.6). Sensitivity analyses confirmed these results using the criteria defined as elevations of the SCr by ?25% and 0.3 mg/dl from the baseline, respectively. In conclusion, CIN was significantly correlated with long-term mortality in patients with CKD but not in those without CKD.
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Evolution in practice patterns and long-term outcomes of coronary revascularization from bare-metal stent era to drug-eluting stent era in Japan.
Am. J. Cardiol.
PUBLISHED: 02-24-2014
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Treatment of coronary artery disease has significantly changed over the past decade including an introduction of drug-eluting stents and a more stringent adherence to evidence-based medications. However, the impact of these advanced treatment methods on the practice patterns and long-term outcomes in patients undergoing coronary revascularization in the real world has not been yet fully evaluated. The present study population consisted of the 2 groups of patients who underwent their first coronary revascularization in the Coronary REvascularization Demonstrating Outcome Study in Kyoto Registry Cohort-1 (bare-metal stent era: January 2000 to December 2002, n = 8,986) and Cohort-2 (drug-eluting stent era: January 2005 to December 2007, n = 10,339). Compared with Cohort-1, the proportion of patients treated with percutaneous coronary intervention significantly increased in Cohort-2 (73% vs 81%, p <0.001), particularly for 3-vessel disease (50% vs 61%, p <0.001) and left main disease (18% vs 36%, p <0.001). Evidence-based medications were more frequently used in Cohort-2. The cumulative 2-year incidence of and the adjusted risk for all-cause death were not significantly different between Cohort-1 and Cohort-2 (6.2% vs 6.4%, p = 0.69, and hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.81 to 1.03, p = 0.15). Adjusted risks for both myocardial infarction and repeated coronary revascularization were significantly reduced in Cohort-2 compared with Cohort-1 (HR 0.80, 95% CI 0.67 to 0.96, p = 0.02, and HR 0.73, 95% CI 0.69 to 0.77, p <0.001, respectively). In conclusion, despite changes in treatment methods over time, the long-term mortality of patients undergoing coronary revascularization in the real-world clinical practice has not been changed, although there was a significant reduction of myocardial infarction and repeated coronary revascularization.
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Anticoagulant and antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention.
Am. J. Cardiol.
PUBLISHED: 02-11-2014
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The prevalence, intensity, safety, and efficacy of oral anticoagulation (OAC) in addition to dual antiplatelet therapy (DAPT) in "real-world" patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not yet been fully evaluated. In the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry cohort-2, a total of 1,057 patients with AF (8.3%) were identified among 12,716 patients undergoing first PCI. Cumulative 5-year incidence of stroke was higher in patients with AF than in no-AF patients (12.8% vs 5.8%, p <0.0001). Although most patients with AF had CHADS2 score ?2 (75.2%), only 506 patients (47.9%) received OAC with warfarin at hospital discharge. Cumulative 5-year incidence of stroke in the OAC group was not different from that in the no-OAC group (13.8% vs 11.8%, p = 0.49). Time in therapeutic range (TTR) was only 52.6% with an international normalized ratio of 1.6 to 2.6, and only 154 of 409 patients (37.7%) with international normalized ratio data had TTR ?65%. Cumulative 5-year incidence of stroke in patients with TTR ?65% was markedly lower than that in patients with TTR <65% (6.9% vs 15.1%, p = 0.01). In a 4-month landmark analysis in the OAC group, there was a trend for higher cumulative incidences of stroke and major bleeding in the on-DAPT (n = 286) than in the off-DAPT (n = 173) groups (15.1% vs 6.7%, p = 0.052 and 14.7% vs 8.7%, p = 0.10, respectively). In conclusion, OAC was underused and its intensity was mostly suboptimal in real-world patients with AF undergoing PCI, which lead to inadequate stroke prevention. Long-term DAPT in patients receiving OAC did not reduce stroke incidence.
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Timing of valve repair for severe degenerative mitral regurgitation and long-term left ventricular function.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 01-31-2014
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Current guidelines recommended surgery for patients with severe degenerative mitral regurgitation (MR) when specific left ventricular (LV) dimensions or ejection fraction (EF) are reached, based on previous postoperative survival studies. The aim of this study was to evaluate the incidence and predictors of long-term postoperative LV dysfunction, and investigate the preoperative parameters necessary to maintain or recover long-term LV function in the era of mitral valve (MV) repair.
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Critical roles of nardilysin in the maintenance of body temperature homoeostasis.
Nat Commun
PUBLISHED: 01-09-2014
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Body temperature homoeostasis in mammals is governed centrally through the regulation of shivering and non-shivering thermogenesis and cutaneous vasomotion. Non-shivering thermogenesis in brown adipose tissue (BAT) is mediated by sympathetic activation, followed by PGC-1? induction, which drives UCP1. Here we identify nardilysin (Nrd1 and NRDc) as a critical regulator of body temperature homoeostasis. Nrd1(-/-) mice show increased energy expenditure owing to enhanced BAT thermogenesis and hyperactivity. Despite these findings, Nrd1(-/-) mice show hypothermia and cold intolerance that are attributed to the lowered set point of body temperature, poor insulation and impaired cold-induced thermogenesis. Induction of ?3-adrenergic receptor, PGC-1? and UCP1 in response to cold is severely impaired in the absence of NRDc. At the molecular level, NRDc and PGC-1? interact and co-localize at the UCP1 enhancer, where NRDc represses PGC-1? activity. These findings reveal a novel nuclear function of NRDc and provide important insights into the mechanism of thermoregulation.
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Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.
PLoS ONE
PUBLISHED: 01-01-2014
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Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.
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MicroRNAs and Lipoprotein Metabolism.
J. Atheroscler. Thromb.
PUBLISHED: 11-19-2013
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MicroRNAs(miRNAs; miRs) are small, non-protein-coding RNAs that negatively regulate the gene expression. They bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recently, some miRNAs have been shown to be involved in lipid homoeostasis. In particular, miR122 and miR-33 have a significant impact on lipid homeostasis and are potential therapeutic targets for treating lipid disorders and/or atherosclerosis. In this review, we describe the current understanding of the function of miRNAs in lipid homeostasis, with a focus on lipoprotein metabolism.
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Impact of occult renal impairment on early and late outcomes following coronary artery bypass grafting.
Interact Cardiovasc Thorac Surg
PUBLISHED: 06-21-2013
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High serum creatinine is considered an independent risk factor for poor outcomes following coronary artery bypass grafting (CABG). However, the impact of occult renal impairment (ORI), defined as an impaired glomerular filtration rate (GFR) with a normal serum creatinine (SCr) level, remains unclear. Thus, we sought to investigate the impact of ORI on outcomes after CABG.
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MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice.
Nat Commun
PUBLISHED: 04-27-2013
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MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports have indicated that miR-33, which is located within the intron of sterol regulatory element-binding protein (SREBP) 2, controls cholesterol homoeostasis and may be a potential therapeutic target for the treatment of atherosclerosis. Here we show that deletion of miR-33 results in marked worsening of high-fat diet-induced obesity and liver steatosis. Using miR-33(-/-)Srebf1(+/-) mice, we demonstrate that SREBP-1 is a target of miR-33 and that the mechanisms leading to obesity and liver steatosis in miR-33(-/-) mice involve enhanced expression of SREBP-1. These results elucidate a novel interaction between SREBP-1 and SREBP-2 mediated by miR-33 in vivo.
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Ultrastructural maturation of human-induced pluripotent stem cell-derived cardiomyocytes in a long-term culture.
Circ. J.
PUBLISHED: 02-09-2013
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In the short- to mid-term, cardiomyocytes generated from human-induced pluripotent stem cells (hiPSC-CMs) have been reported to be less mature than those of adult hearts. However, the maturation process in a long-term culture remains unknown.
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Nardilysin prevents amyloid plaque formation by enhancing ?-secretase activity in an Alzheimers disease mouse model.
Neurobiol. Aging
PUBLISHED: 01-17-2013
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Amyloid beta (A?) peptide, the main component of senile plaques in patients with Alzheimers disease (AD), is derived from proteolytic cleavage of amyloid precursor protein (APP) by ?- and ?-secretases. Alpha-cleavage of APP by ?-secretase has a potential to preclude the generation of A? because it occurs within the A? domain. We previously reported that a metalloendopeptidase, nardilysin (N-arginine dibasic convertase; NRDc) enhances ?-cleavage of APP, which results in the decreased generation of A? in vitro. To clarify the in vivo role of NRDc in AD, we intercrossed transgenic mice expressing NRDc in the forebrain with an AD mouse model. Here we demonstrate that the neuron-specific overexpression of NRDc prevents A? deposition in the AD mouse model. The activity of ?-secretase in the mouse brain was enhanced by the overexpression of NRDc, and was reduced by the deletion of NRDc. However, reactive gliosis adjacent to the A? plaques, one of the pathological features of AD, was not affected by the overexpression of NRDc. Taken together, our results indicate that NRDc controls A? formation through the regulation of ?-secretase.
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Bmp7 maintains undifferentiated kidney progenitor population and determines nephron numbers at birth.
PLoS ONE
PUBLISHED: 01-01-2013
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The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarified. Germline knockout of bone morphogenetic protein 7 (Bmp7) results in massive apoptosis of the kidney progenitor cells and defects in early stages of nephrogenesis. This phenotype has precluded analysis of Bmp7 function in the later stage of nephrogenesis. In this study, utilization of conditional null allele of Bmp7 in combination with systemic inducible Cre deleter mice enabled us to analyze Bmp7 function at desired time points during kidney development, and to discover the novel function of Bmp7 to inhibit the precocious differentiation of the progenitor cells to nephron. Systemic knockout of Bmp7 in vivo after the initiation of kidney development results in the precocious differentiation of the kidney progenitor cells to nephron, in addition to the prominent apoptosis of progenitor cells. We also confirmed that in vitro knockout of Bmp7 in kidney explant culture results in the accelerated differentiation of progenitor population. Finally we utilized colony-forming assays and demonstrated that Bmp7 inhibits epithelialization and differentiation of the kidney progenitor cells. These results indicate that the function of Bmp7 to inhibit the precocious differentiation of the progenitor cells together with its anti-apoptotic effect on progenitor cells coordinately maintains renal progenitor pool in undifferentiated status, and determines the nephron number at birth.
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Persistent overexpression of phosphoglycerate mutase, a glycolytic enzyme, modifies energy metabolism and reduces stress resistance of heart in mice.
PLoS ONE
PUBLISHED: 01-01-2013
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Heart failure is associated with changes in cardiac energy metabolism. Glucose metabolism in particular is thought to be important in the pathogenesis of heart failure. We examined the effects of persistent overexpression of phosphoglycerate mutase 2 (Pgam2), a glycolytic enzyme, on cardiac energy metabolism and function.
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A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents.
Cardiovasc. Res.
PUBLISHED: 12-08-2011
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Short-QT syndrome (SQTS) is a recently recognized disorder associated with atrial fibrillation (AF) and sudden death due to ventricular arrhythmias. Mutations in several ion channel genes have been linked to SQTS; however, the mechanism remains unclear. This study describes a novel heterozygous gain-of-function mutation in the inward rectifier potassium channel gene, KCNJ2, identified in SQTS.
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Predicting long-term mortality after first coronary revascularization: – the Kyoto model –.
Circ. J.
PUBLISHED: 11-17-2011
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We explored the determinants of mortality in order to develop and validate the Kyoto model, which predicts outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).
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Clinical outcomes in non-surgically managed patients with very severe versus severe aortic stenosis.
Heart
PUBLISHED: 09-27-2011
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The management of asymptomatic severe and very severe aortic stenosis (AS) remains unestablished. This study aimed to investigate the clinical outcomes of severe versus very severe AS patients.
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Left atrial volume predicts adverse cardiac and cerebrovascular events in patients with hypertrophic cardiomyopathy.
Cardiovasc Ultrasound
PUBLISHED: 09-26-2011
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To prospectively evaluate the relationship between left atrial volume (LAV) and the risk of clinical events in patients with hypertrophic cardiomyopathy (HCM).
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Detection of intimal defect by 64-row multidetector computed tomography in patients with acute aortic intramural hematoma.
Circulation
PUBLISHED: 09-14-2011
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Previous pathological and clinical studies demonstrated an intimal defect in patients with acute aortic intramural hematoma (IMH). The purpose of this study was to investigate the prevalence and clinical outcome of intimal defect detected by multidetector computed tomography (MDCT) in patients with IMH.
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Low DBP may not be an independent risk for cardiovascular death in revascularized coronary artery disease patients.
J. Hypertens.
PUBLISHED: 08-23-2011
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It remains controversial whether extremely low DBP is a risk for cardiovascular events in patients with coronary artery disease (CAD). Coronary revascularization therapy became prevalent in CAD patients. We sought to determine the impact of low DBP on cardiovascular events and to investigate the predicting factors in revascularized CAD patients.
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Comparison of the psychosocial quality of life in hemodialysis patients between the elderly and non-elderly using a visual analogue scale: the importance of appetite and depressive mood.
Geriatr Gerontol Int
PUBLISHED: 08-15-2011
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The number of hemodialysis (HD) patients is increasing along with their mean age in Japan. The assessment of their psychosocial status and quality of life (QOL) is therefore becoming more and more important along with laboratory data or comorbidities.
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Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice.
J. Mol. Cell. Cardiol.
PUBLISHED: 08-11-2011
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Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD(+)-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.
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Analysis of liver metabolism in a rat model of heart failure.
Int. J. Cardiol.
PUBLISHED: 07-05-2011
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Cachexia, namely body wasting, is a common complication in cases of congestive heart failure (CHF). Although, neurohumoral and immune abnormalities are associated with the condition, precisely how the imbalance of catabolism and anabolism is responsible for the wasting process is not known.
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Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage.
Circ Cardiovasc Genet
PUBLISHED: 06-02-2011
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Recently, elevation of circulating muscle-specific microRNA (miRNA) levels has been reported in patients with acute myocardial infarction. However, it is still unclear from which part of the myocardium or under what conditions miRNAs are released into circulating blood. The purpose of this study was to identify the source of elevated levels of circulating miRNAs and their function in cardiovascular diseases.
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An autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with intestinal bleeding in chronic renal failure.
Ren Fail
PUBLISHED: 06-01-2011
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A 50-year-old man who underwent hemodialysis (HD) at local outpatient HD center due to end-stage renal disease (ESRD) was transferred to our hospital because of pneumonia. He had severe emaciation and past history of congestive heart failure. Presenting symptoms almost consistently involved difficulty in hearing and recurrent attacks of migraine-like headaches. He was diagnosed with dilated cardiomyopathy, showing diastolic mechanical dyssynchrony by tissue Doppler echocardiography. On the day of death, he had hematemesis and hemorrhagic shock. Autopsy revealed perforation of duodenum, and genetic analysis using mitochondrial DNA from cardiac muscle and iliopsoas muscle revealed a 3243A > G mutation in the mitochondrial tRNA(Leu(UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Multiple organ failure due to the mutation of mitochondrial DNA with gastrointestinal bleeding is not a common.
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Successful thrombus aspiration during primary percutaneous coronary intervention reduces infarct size and preserves myocardial viability: a cardiac magnetic resonance imaging study.
J Invasive Cardiol
PUBLISHED: 05-13-2011
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The purpose of this study was to evaluate the influence of thrombus aspiration during primary percutaneous coronary intervention (PCI) on myocardial viability in patients with ST-segment elevation myocardial infarction (STEMI) using cardiac magnetic resonance imaging (MRI).
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Prognostic utility of T-wave alternans in a real-world population of patients with left ventricular dysfunction: the PREVENT-SCD study.
Clin Res Cardiol
PUBLISHED: 05-09-2011
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The predictive value of T-wave alternans (TWA) for lethal ventricular tachyarrhythmia in patients with left ventricular (LV) dysfunction is controversial. Also, long-term arrhythmia risk of patients ineligible for the TWA test is unknown.
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Clinical characteristics and outcomes of Japanese women undergoing coronary revascularization therapy.
Circ. J.
PUBLISHED: 04-12-2011
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Limited data are available for gender-based differences in patients undergoing coronary revascularization. This study aimed to identify gender-based differences in risk factor profiles and outcomes among Japanese patients undergoing coronary revascularization.
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Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice.
J. Clin. Invest.
PUBLISHED: 02-25-2011
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In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis is mediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the reduced production of fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance in chronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstrated that the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelin protein zero-Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In the diseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelial cells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantly contributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated that attenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administration of neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration of tamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well as fibrosis in a mouse model of kidney fibrosis. These findings reveal the pathophysiological roles of P0-Cre lineage-labeled fibroblasts in the kidney and clarify the link between renal fibrosis and renal anemia.
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Activation of Src mediates PDGF-induced Smad1 phosphorylation and contributes to the progression of glomerulosclerosis in glomerulonephritis.
PLoS ONE
PUBLISHED: 02-20-2011
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Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely known. Here we examined the role of c-Src tyrosine kinase in the proliferative change of MCs. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, MC proliferation and type IV collagen (Col4) expression peaked on day 6. Immunohistochemical staining for the expression of phospho-Src (pSrc), phospho-Smad1 (pSmad1), Col4, and smooth muscle ?-actin (SMA) revealed that the activation of c-Src and Smad1 signals in glomeruli peaked on day 6, consistent with the peak of mesangial proliferation. When treated with PP2, a Src inhibitor, both mesangial proliferation and sclerosis were significantly reduced. PP2 administration also significantly reduced pSmad1, Col4, and SMA expression. PDGF induced Col4 synthesis in association with increased expression of pSrc and pSmad1 in cultured MCs. In addition, PP2 reduced Col4 synthesis along with decreased pSrc and pSmad1 protein expression in vitro. Moreover, the addition of siRNA against c-Src significantly reduced the phosphorylation of Smad1 and the overproduction of Col4. These results provide new evidence that the activation of Src/Smad1 signaling pathway plays a key role in the development of glomerulosclerosis in experimental glomerulonephritis.
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Long-term safety and efficacy of sirolimus-eluting stents versus bare-metal stents in real world clinical practice in Japan.
Cardiovasc Interv Ther
PUBLISHED: 01-24-2011
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Long-term safety and efficacy of drug-eluting stents remains controversial. The CREDO-Kyoto registry cohort-2 is a physician-initiated non-company sponsored multi-center registry enrolling consecutive patients undergoing first coronary revascularization in 26 centers in Japan. We compared 3-year outcome between patients treated with sirolimus-eluting stent (SES) only (5092 patients) and bare-metal stent (BMS) only (5405 patients). SES-use as compared with BMS-use was associated with significantly lower adjusted risk for all-cause death [hazard ratio (HR) [95% confidence interval (CI)] 0.72 (0.59-0.87), P = 0.0007], which was mainly driven by the reduction in non-cardiac death [HR (95% CI) 0.64 (0.48-0.85), P = 0.002]. The risk of cardiac death [HR (95% CI) 0.82 (0.63-1.07), P = 0.15], myocardial infarction [HR (95% CI) 0.73 (0.51-1.03), P = 0.07] and definite stent thrombosis [HR (95% CI) 0.62 (0.35-1.09), P = 0.1] was not different between the two groups. Despite longer duration of thienopyridine administration, SES-use was associated with significantly lower risk for bleeding [HR (95% CI) 0.75 (0.6-0.95), P = 0.02] and similar risk for stroke [HR (95% CI) 1.0 (0.75-1.34), P = 1.0]. The risk for target-lesion revascularization (TLR) was markedly lower in the SES group [HR (95% CI) 0.42 (0.36-0.48), P < 0.0001]. The direction and magnitude of the effect of SES relative to BMS in patients presenting acute myocardial infarction (AMI) were similar to those in patients presenting otherwise. In conclusion, SES-use as compared with BMS-use was associated with marked reduction of TLR without any increases in death, myocardial infarction, stent thrombosis, stroke and bleeding in real world clinical practice regardless of clinical presentation including AMI.
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Direct monitoring of mitochondrial calcium levels in cultured cardiac myocytes using a novel fluorescent indicator protein, GCaMP2-mt.
Int. J. Cardiol.
PUBLISHED: 01-11-2011
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An opening of the mitochondrial permeability transition pore (MPTP), which leads to loss of mitochondrial membrane potential (??(m)), is the earliest event that commits a cell to death. Mitochondrial matrix calcium ([Ca(2+)](m)) is considered to be a critical regulator of MPTP, but direct monitoring of [Ca(2+)](m) is difficult with previously-reported sensors. We developed a novel fluorescent indicator for [Ca(2+)](m), GCaMP2-mt, by adding a mitochondrial targeting sequence to a high signal-to-noise Ca(2+) sensor protein GCaMP2, and monitored dynamic changes in oxidant-induced cardiac myocyte death.
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Coronary revascularization in patients with liver cirrhosis.
Ann. Thorac. Surg.
PUBLISHED: 01-07-2011
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Liver cirrhosis is a major risk factor for cardiac surgery using cardiopulmonary bypass. However, percutaneous coronary intervention (PCI) or off-pump coronary artery bypass graft surgery (OPCABG) may be a less invasive alternative strategy.
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Association of the use of proton pump inhibitors with adverse cardiovascular and bleeding outcomes after percutaneous coronary intervention in the Japanese real world clinical practice.
Cardiovasc Interv Ther
PUBLISHED: 01-06-2011
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Previous studies have shown inconsistent results regarding the effects of concomitant use of clopidogrel and proton pump inhibitors (PPI) on cardiovascular outcomes. We sought to evaluate the clinical impact of PPI-use in patients treated with thienopyridines after percutaneous coronary intervention (PCI) in a large Japanese observational database. Among 12446 patients discharged alive on thienopyridines (ticlopidine 90.4% and clopidogrel 9.6%), 3223 patients were treated with PPIs and 9223 patients without PPI at the time of hospital discharge. The PPI group included more patients with co-morbidities than the non-PPI group. The adjusted hazard ratio (HR) of PPI-use for a composite of cardiovascular death, myocardial infarction, and stroke was 1.26 (95% confidence interval (CI) 1.09-1.47, p = 0.002). The adjusted HR of PPI-use for bleeding was 1.26 (95% CI 1.05-1.52, p = 0.013). Cardiovascular and bleeding outcomes were not different among the three groups receiving three different types of PPI. The negative effect of PPI on cardiovascular outcome was consistently seen in both drug-eluting stent (DES) [HR 1.31 (95% CI 1.07-1.6, p = 0.0097)] and non-DES strata [HR 1.25 (95% CI: 0.99-1.57, p = 0.057)] (Interaction p = 0.79) despite the fact that the duration of thienopyridine administration was significantly longer in patients receiving DES. In conclusion, cardiovascular outcomes after PCI were significantly worse in patients with PPI than in patients without PPI in the Japanese real clinical practice. However, the observed poorer cardiovascular outcome in patients receiving PPI was most likely to be related to residual confounding and seemed not causally related to attenuation of antiplatelet effect of thienopyridine through interaction with PPI.
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MicroRNA-27a regulates beta cardiac myosin heavy chain gene expression by targeting thyroid hormone receptor beta1 in neonatal rat ventricular myocytes.
Mol. Cell. Biol.
PUBLISHED: 12-13-2010
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MicroRNAs (miRNAs), small noncoding RNAs, are negative regulators of gene expression and play important roles in gene regulation in the heart. To examine the role of miRNAs in the expression of the two isoforms of the cardiac myosin heavy chain (MHC) gene, ?- and ?-MHC, which regulate cardiac contractility, endogenous miRNAs were downregulated in neonatal rat ventricular myocytes (NRVMs) using lentivirus-mediated small interfering RNA (siRNA) against Dicer, an essential enzyme for miRNA biosynthesis, and MHC expression levels were examined. As a result, Dicer siRNA could downregulate endogenous miRNAs simultaneously and the ?-MHC gene but not ?-MHC, which implied that specific miRNAs could upregulate the ?-MHC gene. Among 19 selected miRNAs, miR-27a was found to most strongly upregulate the ?-MHC gene but not ?-MHC. Moreover, ?-MHC protein was downregulated by silencing of endogenous miR-27a. Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor ?1 (TR?1), which negatively regulates ?-MHC transcription, as a target of miR-27a. Moreover, miR-27a was demonstrated to modulate ?-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with ?-MHC gene upregulation. These findings suggested that miR-27a regulates ?-MHC gene expression by targeting TR?1 in cardiomyocytes.
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Relationships between plasma fatty acid composition and coronary artery disease.
J. Atheroscler. Thromb.
PUBLISHED: 11-17-2010
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The Japan EPA Lipid Intervention Study (JELIS) was the first prospective randomized clinical trial to demonstrate prevention of coronary events by pure eicosapentaenoic acid (EPA). The aim of this study was to examine the relationships between various plasma fatty acid concentrations and the risk of coronary events in JELIS participants.
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MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 09-20-2010
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Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A1 (ABCA1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33-deficient mice showed a marked increase in ABCA1 levels and higher apoA-I-dependent cholesterol efflux than those from WT mice. ABCA1 protein levels in liver were also higher in miR-33-deficient mice than in WT mice. Moreover, miR-33-deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo.
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Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin.
Eur. J. Heart Fail.
PUBLISHED: 09-17-2010
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Insulin-like growth factor (IGF)-I is a regulator of glucose/fatty acid metabolism and may be involved in the pathophysiology of cardiovascular disease, but it remains unclear whether endogenous IGF-I is associated with the prognosis of heart failure (HF). We investigated whether the IGF axis, the ratio of IGF-I to IGF-binding protein-3 (IGFBP-3), was a predictor of clinical outcomes in HF. The association of IGF axis with serum adiponectin level, a prognostic marker of HF as well as a regulator of glucose/fatty acid metabolism, was also analysed.
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Impact of new development of ulcer-like projection on clinical outcomes in patients with type B aortic dissection with closed and thrombosed false lumen.
Circulation
PUBLISHED: 09-15-2010
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The purpose of this study was to investigate the clinical importance of newly developed ulcer-like projection (ULP) in patients with type B aortic dissection with closed and thrombosed false lumen (AD with CTFL), which is better known as aortic intramural hematoma.
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Regulation of adipocyte differentiation by activation of serotonin (5-HT) receptors 5-HT2AR and 5-HT2CR and involvement of microRNA-448-mediated repression of KLF5.
Mol. Endocrinol.
PUBLISHED: 08-18-2010
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Retrovirus insertion-mediated random mutagenesis was applied in 3T3-L1 preadipocyte cells to better understand the molecular basis of obesity (the expansion of individual adipocytes). We found that tryptophan hydroxylase-1, a rate-limiting enzyme for the synthesis of serotonin (5-HT), is expressed in adipocytes and is required for their differentiation. A 5-HT type 2A receptor (5-HT(2A)R) antagonist, ketanserin, and a 5-HT(2c)R antagonist, SB-242084, inhibited adipocyte differentiation. Because 5-HT(2c)R mRNA levels are up-regulated during adipocyte differentiation and micro-RNA (miR)-448 is located in the fourth intron of Htr2c, we also studied the role of miR-448 in 3T3-L1 cells. Through a bioinformatics approach, Krüppel-like factor 5 (KLF5) was identified as a potential target of miR-448. Using a luciferase reporter assay, we confirmed that miR-448 targets the Klf5 3-intranslated region. Overexpression of miR-448 reduced the expression of Klf5 and adipocyte differentiation, which was confirmed by the reduced expression of adipogenic genes and triglyceride accumulation. To examine the loss of miR-448 function, we constructed a decoy gene that had tandem complementary sequences for miR-448 in the 3-untranslated region of a luciferase gene under the control of a cytomegalovirus promoter. When the miR-448 decoy gene was introduced into 3T3-L1 preadipocytes, KLF5 was up-regulated and triglyceride concentration was increased. In this study, we identified the regulation of adipocyte differentiation by 5-HT, 5-HT(2A)R, and 5-HT(2C)R. miR-448-mediated repression of KLF5 was identified as a negative regulator for adipocyte differentiation.
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Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway.
Cardiovasc. Res.
PUBLISHED: 05-21-2010
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A significant increase in congestive heart failure (CHF) was reported when the anti-ErbB2 antibody trastuzumab was used in combination with the chemotherapy drug doxorubicin (Dox). The aim of the present study was to investigate the role(s) of miRNAs in acute Dox-induced cardiotoxicity.
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Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease.
Circ. J.
PUBLISHED: 05-18-2010
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The JELIS trial examined the preventive effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemia. Previous investigators have reported that patients with peripheral artery disease (PAD) have a poor prognosis due to the potential risk for CAD. We conducted a subanalysis to examine whether the incidence of CAD was high in patients with PAD and whether EPA prevented the occurrence of CAD.
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Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts prognosis after acute coronary syndrome--a pilot study.
Circ. J.
PUBLISHED: 05-14-2010
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Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in atherosclerotic plaque vulnerability. It is shed, in part, by proteases and released as soluble LOX-1 (sLOX-1), which is a specific and sensitive biomarker of acute coronary syndrome (ACS). The present study explored if sLOX-1 can also predict prognosis after ACS.
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Atherosclerotic plaques induced by marble-burying behavior are stabilized by exercise training in experimental atherosclerosis.
Int. J. Cardiol.
PUBLISHED: 04-13-2010
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We assessed the hypothesis whether behavioral stress may affect the development of atherosclerosis and whether regular exercise training may influence the composition of atherosclerotic plaques in apolipoprotein (apo) E-deficient mice.
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Characterization of the antiplatelet effect of aspirin at enrollment and after 2-year follow-up in a real clinical setting in Japan.
Circ. J.
PUBLISHED: 04-10-2010
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Aspirin is an antiplatelet drug widely used for the prevention of cardiovascular diseases. It has been reported that some patients who exhibit a reduced antiplatelet effect of aspirin have higher cardiovascular risk. It is still controversial whether the antiplatelet effect of aspirin diminishes after a few years of treatment. This study aimed to evaluate the antiplatelet effect of aspirin and its 2-year change in Japanese patients.
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Flightless-I (Fli-I) regulates the actin assembly activity of diaphanous-related formins (DRFs) Daam1 and mDia1 in cooperation with active Rho GTPase.
J. Biol. Chem.
PUBLISHED: 03-11-2010
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Eukaryotic cells dynamically reorganize the actin cytoskeleton to regulate various cellular activities, such as cell shape change, cell motility, cytokinesis, and vesicular transport. Diaphanous-related formins (DRFs), such as Daam1 and mDia1, play central roles in actin dynamics through assembling linear actin filaments. It has been reported that the GTP-bound active Rho binds directly to DRFs and partially unleashes the intramolecular autoinhibition of DRFs. However, whether proteins other than Rho involve the regulation of the actin assembly activity of DRFs has been unclear. Here, we show that Flightless-I (Fli-I), a gelsolin family protein essential for early development, binds directly to Daam1 and mDia1. Fli-I enhances the intrinsic actin assembly activity of Daam1 and mDia1 in vitro and is required for Daam1-induced actin assembly in living cells. Furthermore, Fli-I promotes the GTP-bound active Rho-mediated relief of the autoinhibition of Daam1 and mDia1. Thus, Fli-I is a novel positive regulator of Rho-induced linear actin assembly mediated by DRFs.
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C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice.
J. Atheroscler. Thromb.
PUBLISHED: 02-24-2010
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Adipose tissue inflammation induced by macrophage infiltration through the MCP-1/CCR2 pathway is considered to play a pivotal role in the development of visceral obesity and insulin resistance. In the present study, therefore, we examined whether pharmacological inhibition of CCR2 is effective against the development of diet-induced metabolic disorders.
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Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure.
Circ Heart Fail
PUBLISHED: 02-22-2010
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Congestive heart failure (CHF) is associated with a change in cardiac energy metabolism. However, the mechanism by which this change is induced and causes the progression of CHF is unclear.
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Effect of baseline glycemic level on long-term cardiovascular outcomes after coronary revascularization therapy in patients with type 2 diabetes mellitus treated with hypoglycemic agents.
Am. J. Cardiol.
PUBLISHED: 02-13-2010
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The present study evaluated the association between preoperative hemoglobin A1c (HbA1c) levels and cardiovascular outcomes in patients with type 2 diabetes mellitus (DM) treated with hypoglycemic agents and undergoing coronary revascularization. We conducted a multicenter registry of Japanese patients undergoing first elective coronary revascularization. The present study included 3,571 patients whose HbA1c value at the index hospitalization was available. Of the 3,571 patients, 2,067 did not have DM and 1,504 had type 2 DM. Of the patients with type 2 DM, 202 had a HbA1c level of <6% (very low HbA1c group [VLG]), 426 had a HbA1c level of > or =6% but <7% (low HbA1c group), 405 had a HbA1c level of 7% but <8% (intermediate HbA1c group), and 471 had a HbA1c level of > or =8% (high HbA1c group). The patients with type 2 DM treated with diet only were not included in the present study. The VLG had the lowest rate of freedom from major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. On multivariate analyses, the low HbA1c group had the lowest hazard ratio for MACE relative to those without DM (hazard ratio 1.13, 95% confidence interval 0.80 to 1.55). The VLG, intermediate HbA1c group, and high HbA1c group were significantly associated with an increased risk of MACE. On multivariate analyses of patients with DM using the low HbA1c group as a reference, a high HbA1c group level was significantly associated with an increased risk of MACE. The VLG and intermediate HbA1c group tended to be associated with an increased risk of MACE (VLG, hazard ratio 1.54, 95% confidence interval 0.98 to 2.40; intermediate HbA1c group, hazard ratio 1.44, 95% confidence interval 0.98 to 2.13). In conclusion, patients with type 2 DM treated with hypoglycemic agents and undergoing first elective coronary revascularization had significantly worse cardiovascular outcomes than patients without DM, except for patients with DM and a HbA1c of 6% to 7%. In the patients with DM, those with a HbA1c of 6% to 7% tended to have the lowest risk of MACE.
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Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.
J. Clin. Invest.
PUBLISHED: 02-08-2010
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The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3-/- mice, which model Alport syndrome. Ablation of Usag1 in Col4a3-/- mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3-/- mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.
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Soluble lectin-like oxidized LDL receptor-1 (sLOX-1) as a sensitive and specific biomarker for acute coronary syndrome--comparison with other biomarkers.
J Cardiol
PUBLISHED: 01-20-2010
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Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) appears to be involved in atherosclerotic plaque vulnerability and rupture. Circulating soluble LOX-1 (sLOX-1) levels are dramatically elevated in patients with acute coronary syndrome (ACS), and its diagnostic sensitivity and specificity is superior to high-sensitivity C-reactive protein (hs-CRP). In this study, we have compared the diagnostic value of sLOX-1 for ACS with those of troponin T (TnT) and heart-type fatty acid binding protein (H-FABP).
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Difference in patient profiles and outcomes in Japanese versus American patients undergoing coronary revascularization (collaborative study by CREDO-Kyoto and the Texas Heart Institute Research Database).
Am. J. Cardiol.
PUBLISHED: 01-20-2010
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Although coronary revascularization is common in both Japan and the United States (US), no direct comparison has been performed to demonstrate differences in the clinical characteristics and long-term outcomes of patients in these 2 countries. We analyzed the preprocedural, in-hospital, and long-term data from the Coronary Revascularization Demonstrating Outcome registry (Kyoto, Japan) and the Texas Heart Institute Research Database (Houston, Texas) of 16,100 patients who had undergone elective, initial percutaneous coronary intervention or coronary artery bypass grafting. The Japanese procedures were performed from 2000 to 2002 (n = 8,871, follow-up period 3.5 years, interquartile range 2.6 to 4.3) and the US procedures from 1999 to 2003 (n = 7,229, follow-up period 5.2 years, interquartile range 3.8 to 6.5). The Japanese patients tended to be older (mean age 67.2 vs 62.7 years; p <0.001), to smoke (52.9% vs 46.0%; p <0.001), and to have diabetes (39.2% vs 31.0%; p <0.001) and stroke (16.4% vs 5.0%; p <0.001). The US patients were more obese (body mass index 23.7 vs 29.3 kg/m(2); p <0.001), with greater rates of systemic atherosclerotic disease. Both groups had a similar in-hospital mortality rate (Japanese patients 0.9% vs US patients 1.1%; p = 0.19) and crude long-term mortality rate (Japanese patients 27.7/1,000 person-years, US patients 28.2/1,000 person-years; p = 0.35). After adjustment for known predictors, the US group had greater long-term mortality than the Japanese group (hazard ratio 1.71, 95% confidence interval 1.50 to 1.95; p <0.001). This finding was consistent among all high-risk subgroups. In conclusion, the 2 registries showed similar crude outcomes but important differences in patient risk factors such as obesity. In the adjusted analysis, the Japanese patients had better outcomes than did the US patients. Additional study is needed to assess the effect of ethnic and risk factor variations on coronary artery disease.
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Cyclin-dependent kinase-9 is a component of the p300/GATA4 complex required for phenylephrine-induced hypertrophy in cardiomyocytes.
J. Biol. Chem.
PUBLISHED: 01-17-2010
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A zinc finger protein GATA4 is one of the hypertrophy-responsive transcription factors and forms a complex with an intrinsic histone acetyltransferase, p300. Disruption of this complex results in the inhibition of cardiomyocyte hypertrophy and heart failure in vivo. By tandem affinity purification and mass spectrometric analyses, we identified cyclin-dependent kinase-9 (Cdk9) as a novel GATA4-binding partner. Cdk9 also formed a complex with p300 as well as GATA4 and cyclin T1. We showed that p300 was required for the interaction of GATA4 with Cdk9 and for the kinase activity of Cdk9. Conversely, Cdk9 kinase activity was required for the p300-induced transcriptional activities, DNA binding, and acetylation of GATA4. Furthermore, the kinase activity of Cdk9 was required for the phosphorylation of p300 as well as for cardiomyocyte hypertrophy. These findings demonstrate that Cdk9 forms a functional complex with the p300/GATA4 and is required for p300/GATA4- transcriptional pathway during cardiomyocyte hypertrophy.
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Obesity as a risk factor for coronary events in Japanese patients with hypercholesterolemia on low-dose simvastatin therapy.
J. Atheroscler. Thromb.
PUBLISHED: 01-16-2010
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We previously reported that obesity (defined as a body mass index (BMI) >or=25 kg/m(2)) was not an independent risk factor for coronary heart disease (CHD) in hypercholesterolemic patients without a history of CHD from the Japan Lipid Intervention Trial (J-LIT). In this study, the obese J-LIT subgroup was further analyzed to assess CHD risk.
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Effects of obstructive sleep apnea with intermittent hypoxia on platelet aggregability.
J. Atheroscler. Thromb.
PUBLISHED: 12-22-2009
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Obstructive sleep apnea (OSA) is a risk factor for cardiovascular diseases. Platelets play key roles in the development of atherothrombosis. Several studies assessing platelet activation in patients with OSA have been published; however, there have been only a few studies with a small number of patients with OSA investigating platelet aggregability, which evaluates platelet aggregation more directly than the platelet activation status. We aimed to investigate the effects of OSA and nasal continuous positive airway pressure (nCPAP) therapy, a well-established treatment for OSA, on platelet aggregability.
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MicroRNA-15b modulates cellular ATP levels and degenerates mitochondria via Arl2 in neonatal rat cardiac myocytes.
J. Biol. Chem.
PUBLISHED: 12-10-2009
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MicroRNAs (miRNAs or miRs) are small, non-coding RNAs that modulate mRNA stability and post-transcriptional translation. A growing body of evidence indicates that specific miRNAs can affect the cellular function of cardiomyocytes. In the present study, miRNAs that are highly expressed in the heart were overexpressed in neonatal rat ventricular myocytes, and cellular ATP levels were assessed. As a result, miR-15b, -16, -195, and -424, which have the same seed sequence, the most critical determinant of miRNA targeting, decreased cellular ATP levels. These results suggest that these miRNAs could specifically down-regulate the same target genes and consequently decrease cellular ATP levels. Through a bioinformatics approach, ADP-ribosylation factor-like 2 (Arl2) was identified as a potential target of miR-15b. It has already been shown that Arl2 localizes to adenine nucleotide transporter 1, the exchanger of ADP/ATP in mitochondria. Overexpression of miR-15b, -16, -195, and -424 suppressed the activity of a luciferase reporter construct fused with the 3-untranslated region of Arl2. In addition, miR-15b overexpression decreased Arl2 mRNA and protein expression levels. The effects of Arl2 siRNA on cellular ATP levels were the same as those of miR-15b, and the expression of Arl2 could restore ATP levels reduced by miR-15b. A loss-of-function study of miR-15b resulted in increased Arl2 protein and cellular ATP levels. Electron microscopic analysis revealed that mitochondria became degenerated in cardiomyocytes that had been transduced with miR-15b and Arl2 siRNA. The present results suggest that miR-15b may decrease mitochondrial integrity by targeting Arl2 in the heart.
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Aldosterone signaling associates with p300/GATA4 transcriptional pathway during the hypertrophic response of cardiomyocytes.
Circ. J.
PUBLISHED: 12-07-2009
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Aldosterone exerts its effect by binding to specific mineralocorticoid receptors (MRs). Spironolactone blocks the aldosterone system, which ameliorates heart failure in humans, but the precise molecular mechanisms of MR blockade are unclear.
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Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 10-23-2009
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Great arteries, as well as lungs and skin, contain elastic fibers as important components to maintain their physiological functions. Although recent studies have revealed that a glycoprotein fibulin-4 (FBLN4) is indispensable for the assembly of mature elastic fibers, it remains to be elucidated how FBLN4 takes part in elastogenesis. Here, we report a dose-dependent requirement for FBLN4 in the development of the elastic fibers in arteries, and a specific role of FBLN4 in recruiting the elastin-cross-linking enzyme, lysyl oxidase (LOX). Reduced expression of Fbln4, which was achieved with a smooth muscle-specific Cre-mediated gene deletion, caused arterial stiffness. Electron-microscopic examination revealed disorganized thick elastic laminae with aberrant deposition of elastin. Aneurysmal dilation of the ascending aorta was found when the Fbln4 expression level was reduced to an even lower level, whereas systemic Fbln4 null mice died perinatally from rupture of the diaphragm. We also found a specific interaction between FBLN4 and the propeptide of LOX, which efficiently promotes assembly of LOX onto tropoelastin. These data suggest a mechanism of elastogenesis, in which a sufficient amount of FBLN4 is essential for tethering LOX to tropoelastin to facilitate cross-linking.
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Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice.
Circulation
PUBLISHED: 10-12-2009
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Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging.
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Angio-embolization of renal artery pseudoaneurysm after renal biopsy: a case report.
Ren Fail
PUBLISHED: 10-10-2009
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Renal artery pseudoaneurysm is a rare clinical entity that has been reported after renal biopsy, percutaneous renal surgery, penetrating trauma, and rarely blunt renal trauma. We present the case of a 37-year-old man with ruptured renal artery pseudoaneurysm accompanied by massive gross hematuria, urinary clot retention, and bladder tamponade, which were the presenting signs seven hours after renal biopsy. Abdominal CT scan showed a large perinephric, intracapsular hematoma of left kidney. His angiogram revealed a left renal segmental artery pseudoaneurysm that measured 1 cm x 1 cm. He was successfully treated by selective embolization of the arterial branch supplying the pseudoaneurysm.
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The search for Nkx2-5-regulated genes using purified embryonic stem cell-derived cardiomyocytes with Nkx2-5 gene targeting.
Biochem. Biophys. Res. Commun.
PUBLISHED: 09-24-2009
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Cardiac transcription factors play crucial roles in cardiac development and differentiation. To address the target genes they regulate is important for understanding the molecular mechanisms underlying these processes. In this study, ES cell lines harboring a neomycin resistance gene in the Nkx2-5 gene locus were generated and used to make purified ES cell-derived cardiomyocytes (ESCM) by in vitro differentiation and successive G418 treatment. Three lines with different Nkx2-5 gene expression levels were made and named as Nkx2-5 -/-, +/-, and overexpressing ESCMs. In order to investigate Nkx2-5-regulated gene expression in cardiomyocytes, the gene expression profiles were compared among these lines. The expression patterns of known Nkx2-5 downstream genes were consistent with the previous investigations in vivo. Several genes with Nkx2-5-dependent changes in their expression were detected and confirmed by real-time PCR. This study investigated Nkx2-5-regulated gene expression in ESCM and suggested potential targets of Nkx2-5 in cardiogenesis.
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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.