Early dysregulation of cardiac-specific microRNA-208a is linked to maladaptive cardiac remodelling in diabetic myocardium

BackgroundThe diabetic heart undergoes remodelling contributing to an increased incidence of heart failure in individualswith diabetes at a later stage. The molecular regulators that drive this process in the diabetic heart are still unknown.MethodsReal-time (RT) PCR analysis was performed to determine the expression of cardiac specific microRNA-208a in right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic patients undergoing coronary artery bypass graft surgery. To determine the time-dependent changes, cardiac tissue were collected from type 2 diabetic mice at different age groups. A western blotting analysis was conducted to determine the expression of contractile proteins - and -myosin heavy chain (MHC) and thyroid hormone receptor- (TR-), the negative regulator of -MHC. To determine the beneficial effects of therapeutic modulation of miR-208a, high glucose treated adultmouse HL-1cardiomyocytes were transfected with anti-miR-208a.ResultsRT-PCR analysis showed marked upregulation of miR-208a from early stages of diabetes in type 2 diabetic mouse heart, which was associated with a marked increase in the expression of pro-hypertrophic -MHC and downregulation of TR-. Interestingly, upregulation of miR-208a preceded the switch of -/-MHC isoforms and the development of diastolic and systolic dysfunction. We also observed significant upregulation of miR-208a and modulation of miR-208a associated proteins in the type2 human diabetic heart. Therapeutic inhibition of miR-208a activity in high glucose treated HL-1 cardiomyocytes prevented the activation of -MHC and hence the hypertrophic response.ConclusionOur results provide the first evidence that early modulation of miR-208a in the diabetic heart induces alterations in the downstream signaling pathway leading to cardiac remodelling and that therapeutic inhibition of miR-208a may be beneficial in preventing diabetes-induced adverse remodelling of the heart.