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ABSTRACT: Dysregulated autophagy may lead to the development of disease. Role of autophagy and the diagnostic potential of microRNAs that regulate the autophagy in cardiac hypertrophy have not been evaluated. A rat model of cardiac hypertrophy was established using transverse abdominal aortic constriction (operation group). Cardiomyocyte autophagy was enhanced in rats from the operation group, compared with those in the sham operation group. Moreover, the operation group showed up-regulation of beclin-1 (an autophagy-related gene), and down-regulation of miR-30 in cardiac tissue. The effects of inhibition and over-expression of the beclin-1 gene on the expression of hypertrophy-related genes and on autophagy were assessed. Angiotensin II-induced myocardial hypertrophy was found to be mediated by over-expression of the beclin-1 gene. A dual luciferase reporter assay confirmed that beclin-1 was a target gene of miR-30a. miR-30a induced alterations in beclin-1 gene expression and autophagy in cardiomyocytes. Treatment of cardiomyocytes with miR-30a mimic attenuated the Angiotensin II-induced up-regulation of hypertrophy-related genes and decreased in the cardiomyocyte surface area. Conversely, treatment with miR-30a inhibitor enhanced the up-regulation of hypertrophy-related genes and increased the surface area of cardiomyocytes induced by Angiotensin II. In addition, circulating miR-30 was elevated in patients with left ventricular hypertrophy, and circulating miR-30 was positively associated with left ventricular wall thickness. Collectively, these above-mentioned results suggest that Angiotensin II induces down-regulation of miR-30 in cardiomyocytes, which in turn promotes myocardial hypertrophy through excessive autophagy. Circulating miR-30 may be an important marker for the diagnosis of left ventricular hypertrophy.
PLoS ONE 01/2013; 8(1):e53950. · 4.09 Impact Factor
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ABSTRACT: The pathogenesis of coronary artery disease (CAD) is closely associated with inflammation, in which human leukocyte antigens (HLA), especially HLA-DR molecules, play important roles. However, whether various HLA-DRB1 alleles can contribute differing susceptibility to CAD has not been elucidated. In this study, we demonstrated a significantly lower frequency of HLA-DRB1*12:02:01 in the CAD group (9.82%) than in controls (18.22%) after age adjustment (odds ratio [OR] = 0.489, p = 0.0036). Logistic regression analysis indicated that carriers of HLA-DRB1*12:02:01 exhibited a lower risk of CAD events after adjustment for age, gender, and other confounders (p = 0.014, OR = 0.526 [95% confidence interval 0.314-0.878]). The female carriers of HLA-DRB1*12:02:01 exhibited a much lower risk of CAD events both before (OR = 0.424, p = 0.0387) and after age adjustment (OR = 0.302, p = 0.0058). In another female cohort, the frequency of HLA-DRB1*12:02:01 also differed between the female CAD group (8.23%) and the female controls (18.75%; OR = 0.389, p = 0.0116). Further analysis indicated that HLA-DRB1*12:02:01 was not frequent in participants with premature CAD or more diseased blood vessels. In summary, our data demonstrate that HLA-DRB1*12:02:01 plays a protective role against CAD in southern Han Chinese, especially in females. The mechanism behind the protective effect requires further exploration.
Human immunology 11/2011; 73(1):122-6. · 2.55 Impact Factor
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ABSTRACT: To increase the accessibility of myogenic cells for cell therapy in the infarcted heart, we identified conditions to improve the reproducible conversion of bone marrow mesenchymal stromal cells (BMSCs) into myogenic cells. Such cells may permit functional regeneration following a myocardial infarction. BMSCs derived from green fluorescent protein (GFP) transgenic rats were co-cultured with neonatal rat cardiomyocytes (1:1, 1:10, 1:20, and 1:40 ratios) for 7 days. Some BMSCs contracted synchronously with the neonatal cardiomyocytes, and exhibited action potentials that were confirmed with current clamp recordings. The myogenic phenotype of the BMSCs was confirmed by immunohistochemical staining and flow cytometry (antibodies against cardiac specific alpha-sarcomeric actinin, Troponin I, MEF-2C). An increase in the number of BMSCs expressing cardiac markers correlated with increasing numbers of neonatal cardiomyocytes in the culture. When BMSCs were co-cultured with DiI-labeled neonatal cardiomyocytes, a small percentage of GFP/DiI/Troponin I triple-positive cells were observed after 7 days. This type of myogenic conversion increased nearly twofold when BMSCs were co-cultured with apoptotic (TNF-alpha-treated) cardiomyocytes. BMSCs co-cultured with cardiomyocytes acquired a functional myogenic phenotype in a dose-dependent manner. Myogenic conversion increased when the BMSCs were cultured with apoptotic cells.
Molecular and Cellular Biochemistry 06/2010; 339(1-2):89-98. · 2.06 Impact Factor
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ABSTRACT: The receptor for advanced glycation end products (RAGE) may play an important role in inflammatory processes and endothelial activation, likely to accelerate the processes of coronary atherosclerotic development, especially in diabetic patients. The factors that regulate arterial expression of RAGE are not completely clear. C-reactive protein (CRP) is identified as a key proinflammatory cytokine in patients with atherosclerosis. Therefore, we tested the hypothesis that RAGE expression in endothelial cells can be upregulated by CRP. Human saphenous vein endothelial cells were incubated with human recombinant CRP, free of sodium azide and endotoxin. RAGE protein expression was measured by flow-cytometric analysis and Western blotting. CRP caused a significant increase in RAGE protein expression at a dose as low as 5 mug/mL, with expression peaking at 24 to 48 hours after CRP incubation. The effects of modified monomeric CRP on RAGE protein expression were comparable with that of native pentameric CRP. At the mRNA level, CRP not only increased RAGE gene expression but also attenuated the degradation of RAGE mRNA. Furthermore, RNA interference of RAGE gene expression significantly decreased the level of macrophage chemoattractant protein 1, a key downstream mediator of CRP activity. Therefore, CRP at concentrations known to predict future vascular events upregulates RAGE expression in human endothelial cells at both the protein and mRNA level. Silencing of the RAGE gene prevents CRP-induced macrophage chemoattractant protein 1 activation. These data reinforce the mechanistic links among inflammation, endothelial dysfunction, and atherothrombosis.
Hypertension 10/2006; 48(3):504-11. · 6.21 Impact Factor
