Upregulation of miR-208a aggravates high-fat-diet induced cardiomyocyte injury by targeting insulin receptor substrate 2/phosphatidylinositol-3-kinases/protein kinase pathway

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Background Previous studies have demonstrated that myocardial function is compromised in obese mice induced by a high-fat-diet (HFD), characterized by elevated levels of miRNA-208a and reduced expression of insulin receptor substrate 2 (IRS-2); however, the precise role of miRNA-208a remains elusive as this study aims to elucidate both its functional significance and underlying mechanisms in myocardial injury. Methods In this study, miR-208a (−/−) knockout and C57BL/6J wild-type mice were allocated into two groups: normal diet and HFD. The cardiomyocytes were isolated from neonatal rats, and the model of cardiomyocyte injury was induced by palmitic acid. The viability of cardiomyocytes was assessed using the Cell-Counting Kit 8, while glucose uptake in cardiomyocytes was measured through a glucose uptake test. Results The hematoxylin and eosin staining results revealed a significant reduction in cardiomyocyte hypertrophy, swelling, and cardiac fibrosis in miR-208a−/− mice fed with an HFD. This effect could be reversed by upregulating miR-208a through agomir treatment. MiR-208a−/− mice treated with either normal diet or HFD exhibited comparable survival rates, while miR-208a−/− mice treated with HFD + agomir showed a significant decrease in survival probability. Importantly, miR-208a upregulation induced cardiomyocyte injury by palmitic acid, while this injury was alleviated through miR-208a downregulation using antagomir. Conclusion The resistance of cardiomyocytes to an HFD was enhanced in miR-208a knockout mice, while the upregulation of miR-208a by agomir exacerbated the susceptibility of cardiomyocytes to HFD through the IRS-2/phosphatidylinositol-3-kinases/protein kinase signaling pathway. Cardiomyocyte injury induced by palmitic acid was mediated by the upregulation of miR-208a, which could be reversed by antagomir.

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