MicroRNA Regualtion and Effects in Diabetic Cardiomyopathy
Diabetic cardiomyopathy refers to a spectrum of cardiac disease that is associated with hyperglycemic and hyperlipidemic states. Beyond contractile and relaxation deficits, diabetic hearts also exhibit greater susceptibility to the detrimental effects of ischemic heart disease, pressure overload and remodeling following myocardial infarction. Thus, a diabetic environment can be considered as one pathological ‘hit’ amongst two or more hits that result in frank cardiac dysfunction or heart failure. Our studies will provide new insights into the pathogenesis of diabetic cardiomyopathy, especially regarding increased sensitivity to myocardial injury and stress. MicroRNAs (miRs) are important endogenous signaling regulators, especially suited to stress responses. However, the role of miRs in cardiac adaptation to lack of insulin, cardiac insulin resistance, metabolic shifts, and stress sensitization (all potential components of the diabetic pathological ‘hit’) has not been adequately characterized.
Our preliminary data suggest that there are distinct, early miR cardiac signatures dependent on diabetes etiology and implicate many novel diabetes-dependent miRs. We propose to extend these findings by identification of the corresponding mRNA targets and by functional assessment of miR-mRNA pairs to identify those which may serve as critical ‘hubs’ in cardiac signaling and whose dysregulation may underlie diabetic cardiomyopathy. Our approach is to use mouse models of type 1 and type 2 diabetes and transcriptome-wide, integrated deep sequencing assays to thoroughly explore the contribution of miRs and their in vivo targeted mRNAs to diabetic cardiac dysfunction. By examining miR and targeted mRNA regulation during early onset and at establishment of chronic disease, these experiments will establish whether miRs and their target mRNAs are dysregulated early in disease progression and make an important contribution to the long-term cardiac phenotype. Furthermore, these studies are expected to illustrate changes in cellular signaling that represent potential causes, not merely effects, of diabetic cardiomyopathy. Functional assays on selected miRs will also serve to highlight which anti-miRs or miR mimics may serve as therapeutic prodrugs in mouse trials.