miR-30c and miR-181a synergistically modulate p53–p21 pathway in diabetes induced cardiac hypertrophy

Abstract

p53-p21 pathway mediates cardiomyocyte hypertrophy and apoptosis and is upregulated in diabetic cardiomyopathy (DbCM). We investigated role of microRNAs in regulating p53-p21 pathway in high glucose (HG)-induced cardiomyocyte hypertrophy and apoptosis. miR-30c and miR-181a were identified to target p53. Cardiac expression of microRNAs was measured in diabetic patients, diabetic rats, and in HG-treated cardiomyocytes. Effect of microRNAs over-expression and inhibition on HG-induced cardiomyocyte hypertrophy and apoptosis was examined. Myocardial expression of p53 and p21 genes was increased and expression of miR-30c and miR-181a was significantly decreased in diabetic patients, DbCM rats, and in HG-treated cardiomyocytes. Luciferase assay confirmed p53 as target of miR-30c and miR-181a. Over-expression of miR-30c or miR-181a decreased expression of p53, p21, ANP, cardiomyocyte cell size, and apoptosis in HG-treated cardiomyocytes. Concurrent over-expression of these microRNAs resulted in greater decrease in cardiomyocyte hypertrophy and apoptosis, suggesting a synergistic effect of these microRNAs. Our results suggest that dysregulation of miR-30c and miR-181a may be involved in upregulation of p53-p21 pathway in DbCM.

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

“…32,33 Not until recent years was P53 identified to play a pathogenic role in DM and its complications. P53 is highly expressed under diabetic condition, contributing to the pathogenesis of DM, 34,35 diabetic cardiomyopathy, 36 nephropathy 22,37 and peripheral artery disease. 38 Here we report the pathogenic effect of P53 on diabetic aortic endothelial dysfunction, with miR-34a to be the mediator.…”

Role of microRNA in diabetic cardiomyopathy: From mechanism to intervention

“…Among the miRNAs miR-21 [60], miR-320 [61], miR-141 [62], miR-30d [58], miR-34a [63], miR-301a [64], miR-451 [65], miR-206, miR-223 [66, 67], miR-483-3p [68], miR-216a, miR-221 [69], miR-195 [70], miR-199a-3p, miR-700, miR-142-3p, miR-24, miR-499-3p, miR-208a and miR-705 [71] have often been found to be upregulated, whereas miR-133a [72, 73], miR-150 [74], miR-29 [75], miR-144 [76], miR-378 [77], miR-499 [50], miR-143, miR-30c, miR-181a [78], miR-9 [79] , miR-23b [80], miR-1, miR-373, miR-20a and miR-220b [71], have been found to be downregulated in under diabetic conditions.…”

“…Moreover, miR-181a and miR-30c were identified to target genes of p53 and p21 which are key regulators of cardiomyocyte hypertrophy but also apoptosis. Both p53 and p21 were found to be upregulated by miR-30c and miR-181a in diabetic cardiomyopathy [78]. Furthermore, enhanced miR-141 in the diabetic heart disturbs the mitochondrial energy production which eventually results in cell death [83].…”

MiR‐144 protects the heart from hyperglycemia‐induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis

“…14,15 Deleterious miRNAs such as miR-208a, miR-451, miR-146a, and miR-200c and protective miRNAs such as miR-133a, miR-30c, miR-21, miR-22, and miR-181a have been found to contribute to diabetic cardiac injury. [16][17][18][19][20][21][22][23] These previous findings suggest that the manipulation of miRNAs may serve as a novel therapeutic approach for targeting heart diseases in diabetes. However, only a limited number of studies on the roles of miRNAs in mitochondrial biogenesis in DCM have been conducted.…”