ABSTRACT
BACKGROUND: Emerging evidence suggests that microRNAs (miRs) could be a potential biomarker to identify early molecular alterations in the heart. HDL are the major carriers for miRs into the circulation. This study tested whether changes in the level of HDL could affect the diagnostic sensitivity of miRs. METHODS AND RESULTS: Peripheral blood samples were collected from 20 diabetic and 22 age and gender matched non-diabetic patients undergoing coronary artery bypass graft (CABG) surgery for ischemic heart disease (IHD). Total RNA was extracted from the separated plasma and stored in -80°C. Reverse transcription and amplification using specific primers against cardio-enriched miR-1, -34a, -126, -133, and -499 showed significant correlation between HDL levels and miR-1, -133 and -499. Importantly, normalization of miR levels with HDL showed a significant downregulation of miR-1, -133 and -499 in diabetic plasma, which was not observed before normalization with HDL levels. CONCLUSION: Normalization of circulating miR levels with HDL increases the diagnostic sensitivity of circulating miRs.
Subject(s)
Circulating MicroRNA/blood , Coronary Artery Bypass , Coronary Artery Disease/blood , Diabetes Mellitus/blood , Lipoproteins, HDL/blood , Aged , Aged, 80 and over , Biomarkers/blood , Coronary Artery Bypass/trends , Coronary Artery Disease/epidemiology , Coronary Artery Disease/surgery , Diabetes Mellitus/epidemiology , Diabetes Mellitus/surgery , Female , Humans , Male , Middle Aged , New Zealand/epidemiologySubject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Cardiomyopathies/genetics , Gene Expression Regulation , MicroRNAs/genetics , RNA/genetics , Stroke Volume/physiology , Child , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Diabetic Cardiomyopathies/etiology , Diabetic Cardiomyopathies/physiopathology , Female , Humans , Male , MicroRNAs/biosynthesis , Ventricular Function, Left/physiologyABSTRACT
BACKGROUND: Diabetic women are five times more likely to develop congestive heart failure compared with two fold for men. The underlying mechanism for this gender difference is not known. Here we investigate the molecular mechanisms responsible for this female disadvantage and attempt safeguarding cardiomyocytes viability and function through restoration of pro-survival Pim-1. METHODS AND RESULTS: Diabetes was induced by injection of streptozotocin in CD1 mice of both genders. Functional and dimensional parameters measurement using echocardiography revealed diastolic dysfunction in female diabetic mice within 8 weeks after STZ-induced diabetes. This was associated with significant downregulation of pro-survival Pim-1 and upregulation of pro-apoptotic Caspase-3, microRNA-1 and microRNA-208a. Male diabetic mice did not show any significant changes at this time point (P < 0.05 vs. female diabetic). Further, the onset of ventricular remodelling was quicker in female diabetic mice showing marked left ventricular dilation, reduced ejection fraction and poor contractility (P < 0.05 vs. male diabetic at 12 and 16 weeks of STZ-induced diabetes). Molecular analysis of samples from human diabetic hearts confirmed the results of pre-clinical studies, showing marked downregulation of Pim-1 in the female diabetic heart (P < 0.05 vs. male diabetic). Finally, in vitro restoration of Pim-1 reversed the female disadvantage in diabetic cardiomyocytes. CONCLUSIONS: We provide novel insights into the molecular mechanisms behind the rapid onset of cardiomyopathy in female diabetics. These results suggest the requirement for the development of gender-specific treatments for diabetic cardiomyopathy.
