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Find video protocols related to scientific articles indexed in Pubmed.
Osteopontin: A novel regulator at the cross roads of inflammation, obesity and diabetes.
Mol Metab
PUBLISHED: 07-01-2014
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Since its first description more than 20 years ago osteopontin has emerged as an active player in many physiological and pathological processes, including biomineralization, tissue remodeling and inflammation. As an extracellular matrix protein and proinflammatory cytokine osteopontin is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Modulation of immune cell response by osteopontin has been associated with various inflammatory diseases and may play a pivotal role in the development of adipose tissue inflammation and insulin resistance. Here we summarize recent findings on the role of osteopontin in metabolic disorders, particularly focusing on diabetes and obesity.
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Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis.
Stem Cells
PUBLISHED: 03-17-2014
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The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In this study, we used bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Reconstitution of lethally irradiated apoE(-/-) mice with NOR1-deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C(+) monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C(+) monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local proatherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation.
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Nuclear receptor 4a3 (nr4a3) regulates murine mast cell responses and granule content.
PLoS ONE
PUBLISHED: 01-01-2014
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Nuclear receptor 4a3 (Nr4a3) is a transcription factor implicated in various settings such as vascular biology and inflammation. We have recently shown that mast cells dramatically upregulate Nuclear receptor 4a3 upon activation, and here we investigated the functional impact of Nuclear receptor 4a3 on mast cell responses. We show that Nuclear receptor 4a3 is involved in the regulation of cytokine/chemokine secretion in mast cells following activation via the high affinity IgE receptor. Moreover, Nuclear receptor 4a3 negatively affects the transcript and protein levels of mast cell tryptase as well as the mast cell's responsiveness to allergen. Together, these findings identify Nuclear receptor 4a3 as a novel regulator of mast cell function.
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Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.
Sci Transl Med
PUBLISHED: 11-01-2013
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We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
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Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.
Curr Atheroscler Rep
PUBLISHED: 05-01-2013
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Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling.
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Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis.
Curr Atheroscler Rep
PUBLISHED: 02-21-2013
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Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling.
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Relevance of angiotensin II-induced aortic pathologies in mice to human aortic aneurysms.
Ann. N. Y. Acad. Sci.
PUBLISHED: 12-26-2011
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Angiotensin II infusion in mice promotes abdominal and thoracic aortic aneurysms, which provides a feasible approach to study the mechanisms of these two distinct diseases.
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Regulation of peroxisome proliferator-activated receptor-? by angiotensin II via transforming growth factor-?1-activated p38 mitogen-activated protein kinase in aortic smooth muscle cells.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 11-17-2011
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Peroxisome proliferator-activated receptor-? (PPAR?) ligands attenuate angiotensin II (Ang II)-induced atherosclerosis through interactions with vascular smooth muscle cell (VSMC)-specific PPAR? in hypercholesterolemic mice. Therefore, the purpose of this study was to determine the mechanism of Ang II-mediated intracellular regulation of PPAR? in VSMCs.
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Glutathione depletion prevents diet-induced obesity and enhances insulin sensitivity.
Obesity (Silver Spring)
PUBLISHED: 09-29-2011
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Excessive accumulation of reactive oxygen species (ROS) in adipose tissue has been implicated in the development of insulin resistance and type 2 diabetes. However, emerging evidence suggests a physiologic role of ROS in cellular signaling and insulin sensitivity. In this study, we demonstrate that pharmacologic depletion of the antioxidant glutathione in mice prevents diet-induced obesity, increases energy expenditure and locomotor activity, and enhances insulin sensitivity. These observations support a beneficial role of ROS in glucose homeostasis and warrant further research to define the regulation of metabolism and energy balance by ROS.
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Ghrelin Receptor Deficiency does not Affect Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor-Null Mice.
Front Endocrinol (Lausanne)
PUBLISHED: 09-13-2011
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Objective: Ghrelin, a stomach-derived, secreted peptide, and its receptor (growth hormone secretagogue receptor, GHSR) are known to modulate food intake and energy homeostasis. The ghrelin system is also expressed broadly in cardiovascular tissues. Since ghrelin has been associated with anti-inflammatory and anti-atherogenic properties, but is also well known to promote obesity and impair glucose metabolism, we investigated whether ghrelin has any impact on the development of atherosclerosis. The hypothesis that endogenous ghrelin signaling may be involved in atherosclerosis has not been tested previously. Methods and Results: We crossed ghrelin receptor knockout mice (GHSr(-/-)) into a low-density lipoprotein receptor-null (Ldlr(-/-)) mouse line. In this model, atherosclerotic lesions were promoted by feeding a high-fat, high-cholesterol Western-type diet for 13?months, following a standard protocol. Body composition and glucose homeostasis were similar between Ldlr(-/-) and Ldlr/GHSR(-/-)ko mice throughout the study. Absence or presence of GHSr did not alter the apolipoprotein profile changes in response to diet exposure on an LDLRko background. Atherosclerotic plaque volume in the aortic arch and thoracic aorta were also not affected differentially in mice without ghrelin signaling due to GHSR gene disruption as compared to control LDLRko littermates. In light of the associations reported for ghrelin with cardiovascular disease in humans, the lack of a phenotype in these loss-of-function studies in mice suggests no direct role for endogenous ghrelin in either the inhibition or the promotion of diet-induced atherosclerosis. Conclusion: These data indicate that, surprisingly, the complex and multifaceted actions of endogenous ghrelin receptor mediated signaling on the cardiovascular system have minimal direct impact on atherosclerotic plaque progression as based on a loss-of-function mouse model of the disease.
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Transcriptional regulation of S phase kinase-associated protein 2 by NR4A orphan nuclear receptor NOR1 in vascular smooth muscle cells.
J. Biol. Chem.
PUBLISHED: 08-25-2011
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Members of the NR4A subgroup of the nuclear hormone receptor superfamily have emerged as key transcriptional regulators of proliferation and inflammation. NOR1 constitutes a ligand-independent transcription factor of this subgroup and induces cell proliferation; however, the transcriptional mechanisms underlying this mitogenic role remain to be defined. Here, we demonstrate that the F-box protein SKP2 (S phase kinase-associated protein 2), the substrate-specific receptor of the ubiquitin ligase responsible for the degradation of p27(KIP1) through the proteasome pathway, constitutes a direct transcriptional target for NOR1. Mitogen-induced Skp2 expression is silenced in vascular smooth muscle cells (VSMC) isolated from Nor1-deficient mice or transfected with Nor1 siRNA. Conversely, adenovirus-mediated overexpression of NOR1 induces Skp2 expression in VSMC and decreases protein abundance of its target p27. Transient transfection experiments establish that NOR1 transactivates the Skp2 promoter through a nerve growth factor-induced clone B response element (NBRE). Electrophoretic mobility shift and chromatin immunoprecipitation assays further revealed that NOR1 is recruited to this NBRE site in the Skp2 promoter in response to mitogenic stimulation. In vivo Skp2 expression is increased during the proliferative response underlying neointima formation, and this transcriptional induction depends on the expression of NOR1. Finally, we demonstrate that overexpression of Skp2 rescues the proliferative arrest of Nor1-deficient VSMC. Collectively, these results characterize Skp2 as a novel NOR1-regulated target gene and detail a previously unrecognized transcriptional cascade regulating mitogen-induced VSMC proliferation.
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Race-ethnicity as an effect modifier of the association between HbAlc and mortality in U.S. adults without diagnosed diabetes.
Eur. J. Endocrinol.
PUBLISHED: 05-26-2011
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HbAlc is increasingly appreciated as a risk factor for all-cause and cardiovascular disease (CVD) mortality in the non-diabetic population. In this study, we investigated the association between HbAlc and mortality with a particular focus on the impact of race-ethnicity. Design Cohort study.
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Oxidative stress accumulates in adipose tissue during aging and inhibits adipogenesis.
PLoS ONE
PUBLISHED: 03-11-2011
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Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G(1)?S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction.
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Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 01-13-2011
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Proliferation of smooth muscle cells (SMC) in response to vascular injury is central to neointimal vascular remodeling. There is accumulating evidence that histone acetylation constitutes a major epigenetic modification for the transcriptional control of proliferative gene expression; however, the physiological role of histone acetylation for proliferative vascular disease remains elusive.
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Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 11-24-2010
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Telomerase serves as a critical regulator of tissue renewal. Although telomerase activity is inducible in response to various environmental cues, it remains unknown whether telomerase is activated during the inflammatory remodeling underlying atherosclerosis formation. To address this question, we investigated in the present study the regulation of telomerase in macrophages and during atherosclerosis development in low-density lipoprotein receptor-deficient mice.
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Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 11-18-2010
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Abdominal aortic aneurysms (AAA) are an age-related vascular disease and an important cause of morbidity and mortality. In this study, we sought to determine whether the catalytic component of telomerase, telomerase reverse transcriptase (TERT), modulates angiotensin (Ang) II-induced AAA formation.
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Group X secretory phospholipase A2 negatively regulates ABCA1 and ABCG1 expression and cholesterol efflux in macrophages.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 09-17-2010
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GX sPLA(2) potently hydrolyzes plasma membranes to generate lysophospholipids and free fatty acids; it has been implicated in inflammatory diseases, including atherosclerosis. To identify a novel role for group X (GX) secretory phospholipase A(2) (sPLA(2)) in modulating ATP binding casette transporter A1 (ABCA1) and ATP binding casette transporter G1 (ABCG1) expression and, therefore, macrophage cholesterol efflux.
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Pioglitazone-induced reductions in atherosclerosis occur via smooth muscle cell-specific interaction with PPAR{gamma}.
Circ. Res.
PUBLISHED: 08-26-2010
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Peroxisome proliferator-activated receptor (PPAR)? agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPAR?, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs).
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NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 07-16-2010
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Members of the nuclear hormone receptor superfamily, including the peroxisome proliferator-activated receptor and the liver X receptor subfamilies, orchestrate transcriptional networks involved in the control of metabolism and the development of vascular disease. In addition to these well-characterized ligand-activated transcription factors, the nuclear receptor (NR) superfamily comprises many orphan receptors, whose ligands and physiological functions remain unknown. Among this group of orphan receptors is the NR4A subfamily, including Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3). These orphan NRs constitute an evolutionary ancient and highly conserved group of transcription factors. In contrast to other members of the superfamily, NR4A receptors function as ligand-independent transcription factors and immediate- or early-response genes, which are rapidly induced by a pleiotropy of environmental cues. Early functional studies have pointed to a critical role of NR4A receptors in regulating differentiation, proliferation, and apoptosis. More recent research has characterized NR4A receptors as key transcriptional regulators of glucose and lipid homeostasis, adipogenesis, inflammation, and vascular remodeling. In this review, we will summarize recent advances in understanding the molecular biology and physiological functions of NR4A receptors and discuss their role in the transcriptional control of metabolism and vascular remodeling.
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Deficiency of telomerase activity aggravates the blood-brain barrier disruption and neuroinflammatory responses in a model of experimental stroke.
J. Neurosci. Res.
PUBLISHED: 06-22-2010
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Epidemiology and genetic studies indicate that patients with telomere length shorter than average are at higher risk of dying from heart disease or stroke. Telomeres are located at the ends of eukaryotic chromosomes, which demonstrate progressive length reduction in most somatic cells during aging. The enzyme telomerase can compensate for telomere loss during cell replication. The present study sought to investigate the contribution of telomerase to stroke and blood-brain barrier (BBB) dysfunction. Telomerase reverse transcriptase knockout (TERT(-/-)) mice and littermate controls with normal TERT expression were subjected to a 24-hr permanent middle cerebral artery occlusion (pMCAO). The stroke outcomes were assessed in terms of neurological scores and infarct volumes. In addition, we evaluated oxidative stress, permeability across the BBB, and integrity of tight junctions in brain microvessels. Neurological testing revealed that TERT(-/-) mice showed enhanced deficits compared with controls. These changes were associated with a greater infarct volume. The expression of tight junction protein ZO-1 decreased markedly in ischemic hemispheres of TERT(-/-) mice. The brain microvessels of TERT(-/-) mice also were more susceptible to oxidative stress, revealing higher superoxide and lower glutathione levels compared with mice with normal TERT expression. Importantly, TERT deficiency potentiated the production of inflammatory mediators, such as tumor necrosis factor-alpha, interleukin-1 beta, and intercellular adhesion molecule-1, in the ischemic hemispheres of mice with pMCAO. Our study suggests that TERT deficiency can predispose to the development of stroke in an experimental model of this disease.
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Deficiency of the NR4A orphan nuclear receptor NOR1 decreases monocyte adhesion and atherosclerosis.
Circ. Res.
PUBLISHED: 06-17-2010
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The orphan nuclear receptor NOR1 is a member of the evolutionary highly conserved and ligand-independent NR4A subfamily of the nuclear hormone receptor superfamily. Members of this subfamily have been characterized as early response genes regulating essential biological processes including inflammation and proliferation; however, the role of NOR1 in atherosclerosis remains unknown.
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Intensive glycemic control and cardiovascular disease: an update.
Nat Rev Cardiol
PUBLISHED: 04-20-2010
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Cardiovascular complications constitute the major cause of morbidity and mortality in patients with diabetes. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) provided consistent evidence that intensive glycemic control prevents the development and progression of microvascular complications in patients with type 1 or type 2 diabetes. However, whether intensive glucose lowering also prevents macrovascular disease and major cardiovascular events remains unclear. Extended follow-up of participants in these studies demonstrated that intensive glycemic control reduced the long-term incidence of myocardial infarction and death from cardiovascular disease. By contrast, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, and Veterans Affairs Diabetes Trial (VADT) results suggested that intensive glycemic control to near normoglycemia had either no, or potentially even a detrimental, effect on cardiovascular outcomes. This article discusses the effects of intensive glycemic control on cardiovascular disease, and examines key differences in the design of these trials that might have contributed to their disparate findings. Recommendations from the current joint ADA, AHA, and ACCF position statement on intensive glycemic control and prevention of cardiovascular disease are highlighted.
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Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial migration of HIV-1-infected cells.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 02-05-2010
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Telomerase, via its catalytic component telomerase reverse transcriptase (TERT), extends telomeres of eukaryotic chromosomes. The importance of this reaction is related to the fact that telomere shortening is a rate-limiting mechanism for human life span that induces cell senescence and contributes to the development of age-related pathologies. The aim of the present study was to evaluate whether the modulation of telomerase activity can influence human immunodeficiency virus type 1 (HIV-1)-mediated dysfunction of human brain endothelial cells (hCMEC/D3 cells) and transendothelial migration of HIV-1-infected cells. Telomerase activity was modulated in hCMEC/D3 cells via small interfering RNA-targeting human TERT (hTERT) or by using a specific pharmacological inhibitor of telomerase, TAG-6. The inhibition of hTERT resulted in the upregulation of HIV-1-induced overexpression of intercellular adhesion molecule-1 via the nuclear factor-kappaB-regulated mechanism and induced the transendothelial migration of HIV-1-infected monocytic U937 cells. In addition, the blocking of hTERT activity potentiated a HIV-induced downregulation of the expression of tight junction proteins. These results were confirmed in TERT-deficient mice injected with HIV-1-specific protein Tat into the cerebral vasculature. Further studies revealed that the upregulation of matrix metalloproteinase-9 is the underlying mechanisms of disruption of tight junction proteins in hCMEC/D3 cells with inhibited TERT and exposed to HIV-1. These results indicate that the senescence of brain endothelial cells may predispose to the HIV-induced upregulation of inflammatory mediators and the disruption of the barrier function at the level of the brain endothelium.
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A new glucagon and GLP-1 co-agonist eliminates obesity in rodents.
Nat. Chem. Biol.
PUBLISHED: 06-05-2009
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We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.
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Deficiency of the NR4A neuron-derived orphan receptor-1 attenuates neointima formation after vascular injury.
Circulation
PUBLISHED: 01-19-2009
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The neuron-derived orphan receptor-1 (NOR1) belongs to the evolutionary highly conserved and most ancient NR4A subfamily of the nuclear hormone receptor superfamily. Members of this subfamily function as early-response genes regulating key cellular processes, including proliferation, differentiation, and survival. Although NOR1 has previously been demonstrated to be required for smooth muscle cell proliferation in vitro, the role of this nuclear receptor for the proliferative response underlying neointima formation and target genes trans-activated by NOR1 remain to be defined.
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NR4A Orphan Nuclear Receptors in Cardiovascular Biology.
Drug Discov Today Dis Mech
PUBLISHED: 01-01-2009
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The NR4A orphan nuclear receptor subfamily is comprised of the highly homologous receptors Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3). These evolutionarily conserved and ancient receptors function as ligand-independent transcription factors that regulate the expression of overlapping target genes. As early response genes, the basal expression level of these receptors is low but rapidly induced as a result of changes in environmental cues. The transcriptional activity of these receptors is primarily regulated by gene induction and posttranslational modifications of the receptor including phosphorylation. NR4A receptors were initially identified in the brain and early functional studies suggested a role for these receptors in signal- and cell-specific stimulation of both apoptosis and proliferation. More recent studies have revealed much broader functions of these orphan receptors including the regulation of genes involved in cancer, metabolism, energy balance, atherosclerosis, and vascular remodeling. In this review, we will discuss our current understanding of the molecular biology of NR4A receptors and summarize recent studies suggesting an important role of these orphan receptors in vascular biology.
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Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy.
J. Am. Soc. Nephrol.
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Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.
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Novel mechanisms of abdominal aortic aneurysms.
Curr Atheroscler Rep
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Abdominal aortic aneurysms (AAAs) are a common but asymptomatic disease that has high susceptibility to rupture. Current therapeutic options are limited to surgical procedures because no pharmacological approaches have been proven to decrease either expansion or rupture of human AAAs. The current dearth of effective medical treatment is attributed to insufficient understanding of the mechanisms underlying the initiation, propagation and rupture of AAAs. This review will emphasize recent advances in mechanistic studies that may provide insights into potential pharmacological treatments for this disease. While we primarily focus on recent salient findings, we also discuss mechanisms that continue to be controversial depending on models under study. Despite the progress on exploring mechanisms of experimental AAAs, ultimate validation of mechanisms will require completion of prospective double-blinded clinical trials. In addition, we advocate increased emphasis of collaborative studies using animal models and human tissues for determination of mechanisms that explore expansion and rupture of existing AAAs.
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Involvement of the renin-angiotensin system in abdominal and thoracic aortic aneurysms.
Clin. Sci.
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Aortic aneurysms are relatively common maladies that may lead to the devastating consequence of aortic rupture. AAAs (abdominal aortic aneurysms) and TAAs (thoracic aortic aneurysms) are two common forms of aneurysmal diseases in humans that appear to have distinct pathologies and mechanisms. Despite this divergence, there are numerous and consistent demonstrations that overactivation of the RAS (renin-angiotensin system) promotes both AAAs and TAAs in animal models. For example, in mice, both AAAs and TAAs are formed during infusion of AngII (angiotensin II), the major bioactive peptide in the RAS. There are many proposed mechanisms by which the RAS initiates and perpetuates aortic aneurysms, including effects of AngII on a diverse array of cell types and mediators. These experimental findings are complemented in humans by genetic association studies and retrospective analyses of clinical data that generally support a role of the RAS in both AAAs and TAAs. Given the lack of a validated pharmacological therapy for any form of aortic aneurysm, there is a pressing need to determine whether the consistent findings on the role of the RAS in animal models are translatable to humans afflicted with these diseases. The present review compiles the recent literature that has shown the RAS as a critical component in the pathogenesis of aortic aneurysms.
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Transient exposure of neonatal female mice to testosterone abrogates the sexual dimorphism of abdominal aortic aneurysms.
Circ. Res.
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Abdominal aortic aneurysms (AAAs) exhibit marked sexual dimorphism with higher prevalence in men. Similarly, AAAs induced by angiotensin II (AngII) infusion into mice exhibit a higher prevalence in males. Testosterone promotes AAA pathology in adult male mice through regulation of angiotensin type 1A receptors (AT1aR) in abdominal aortas. However, mechanisms for sexual dimorphism of regional aortic angiotensin receptor expression and AAA formation are unknown.
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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.

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

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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.