Cardiovascular microRNAs: early modulators in the pathogenesis of diabetic heart disease
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Cardiovascular diseases (CVDs) are the major complications and causes of mortality in persons with diabetes,and many factors including hypertension,obesity,atherosclerosis,dyslipidemia,microalbuminuria,endothelial dysfunction,platelet hyperaggregability,coagulation abnormalities,and diabetic cardiomyopathy,contribute to this high prevalence of CVDs.The molecular mechanisms of atherosclerosis,dyslipidemia,and especially endothelial dysfunction,leading to cardiovascular diseases in diabetes are reviewed briefly.
Dyslipidemia
Endothelial Dysfunction
Microalbuminuria
Diabetic Cardiomyopathy
Pathogenesis
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Cardiovascular diseases exist across all developed countries. Biomarkers that can predict or diagnose diseases early in their pathogeneses can reduce their morbidity and mortality in afflicted individuals. microRNAs are small regulatory RNAs that modulate translation and have been identified as potential fluid-based biomarkers across numerous maladies. We describe the current state of cardiovascular disease biomarkers across a range of diseases, including myocardial infarction, acute coronary syndrome, myocarditis, hypertension, heart failure, heart transplantation, aortic stenosis, diabetic cardiomyopathy, atrial fibrillation, and sepsis. We present the current understanding of microRNAs as possible biomarkers in these categories and where their best opportunities exist to enter clinical practice.
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Cardiovascular disease is the leading cause of death in patients with diabetes. Among coronary vascular defects, obstructive coronary artery disease (CAD) is the primary cause of cardiac mortality. However, there is growing evidence that patients with coronary microvascular disease (CMD, also known as non-obstructive coronary disease) also experience chest pain and occasional heart attack. Furthermore, recent studies show that diabetes is the risk factor of CMD. However, the molecular mechanisms by which diabetes develops CMD is not fully understood. MicroRNAs (miRNAs) are a non-coding small RNA that regulates gene expression at the post-transcriptional level, and the change of miRNA profile is implicated in many diseases. In this study, we identified the core miRNAs which are involved in the development of coronary endothelial dysfunction in diabetes. We used an inducible type 2 diabetic (T2D) mouse model generated by high-fat diet and a single injection of low-dose streptozotocin. Our T2D mice did not show detectable atherosclerotic plaque, but developed CMD evidenced by reduced coronary flow velocity reserve. We conducted a miRNA array using mouse coronary endothelial cells (MCECs) isolated from diabetic and control mice, and selected seven miRNAs based on the result. Next, real-time PCR assays were carried out with seven miRNAs and found that miR210 and miR342-5p were downregulated, and miR378 was upregulated in MCECs of diabetic mice compared to the control. To identify the target genes of miR342-5p and miR378, we inhibited miR342-5p or overexpressed miR378 in MCECs. After testing 93 genes that are involved in endothelial functions, we found that inhibition of miR342-5p decreased the levels of Atp2a3 , Opa1 , Sod3 , and Vegfb , whereas miR378 overexpression significantly decreased Aggf1, HK1, Mapk3, Pak1, Panx1, Stim1, Stim2, Vcam1, and Vegfb and increased Casp2 and Gja1 . Western blotting data revealed that the expression levels of Affg1, Opa1, and Pak1 were significantly decreased in the MCECs from diabetic mice compared to the control. In summary, these data suggest that miR342-5p and miR378 could be a potential therapeutic target for CMD in diabetic patients, and Affg1 Opa1 and Pak1 are the downstream mRNAs of miR342-5p or miR378.
Endothelial Dysfunction
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Diabetic, depressive, and cardiovascular disorders are leading causes of morbidity. In diabetics, symptoms of depression are associated with increased clinical complications. Diabetes mellitus is a major risk factor of cardiovascular diseases (CVDs). The vascular depression hypothesis suggests that CVD can increase the risk of depression or exacerbate depression-related conditions. Several studies found a strong correlation between depression and pre-existing vascular disease and vice versa. Recent studies implicate microvascular dysfunction in the pathophysiology of depression and CVD. In addition, microRNAs are potent regulators of gene expression in physiological and pathophysiological processes affecting the microcirculation. We propose an interaction between diabetes mellitus, depression, and CVD involving changes in microcirculation and microRNA expression. Hence, studies are warranted to develop novel microRNA therapeutics and biomarkers to identify diabetic patients at increased risk of developing clinical complications of depression.
Depression
Pathophysiology
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Obesity remains a global problem in modern society. It is commonly associated with an increased risk of cardiovascular diseases (CVD). The search for specific and sensitive biomarkers of CVD continues. Currently, a lot of studies focused on the potential role of microRNA (miRNA) in CVD development and progression. MiRNAs are involved in various pathological disorders associated with CVD. Endothelial dysfunction is considered as the initial step in the pathogenesis of many CVD, and atherosclerosis in particular. Altered expression of several miRNAs is associated with the development of endothelial dysfunction. Some miRNAs are considered as potential therapeutic targets. Further studies to evaluate the role of miRNAs in the pathogenesis of CVD are needed. It will improve the diagnosis and treatment of CVD in patients with obesity.
Pathogenesis
Endothelial Dysfunction
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