miR-132 inhibition improves cardiac remodeling and function in a two-hit mouse model of heart failure with a preserved ejection fraction.

To investigate the impact of antimiR-132, a miR-132 antisense inhibitor, on cardiac remodeling and function in a two-hit mouse model of heart failure with preserved ejection fraction (HFpEF), as well as its underlying mechanism. Male C57BL/6 mice were fed N(omega)-nitro-L-arginine methyl ester plus a high-fat diet to establish an HFpEF model, and then intraperitoneally injected with antimiR-132 or normal saline. Cardiac fibroblasts treated with transforming growth factor β1 (TGF-β1) were cultured in the presence of antimiR-132 or vehicle to examine collagen synthesis and potential mechanisms. Compared to control mice, HFpEF mice showed significant increases in blood pressure, triglycerides, cholesterol, body weight, myocardial hypertrophy, and fibrosis. They also had elevated E/E' ratios and plasma NT-proBNP levels. antimiR-132 did not significantly impact blood pressure or metabolic parameters in HFpEF mice; however, it notably ameliorated myocardial hypertrophy and fibrosis, while concurrently reducing E/E' ratios and plasma NT-proBNP levels. Mechanistically, the cardioprotective effects of antimiR-132 were accompanied by inhibition of the upregulated expression of miR-132 and P-Smad3 protein in the myocardium, as well as reduction in TGF-β1-induced collagen synthesis and Smad3 phosphorylation in cardiac fibroblasts. Taken together, miR-132 inhibition ameliorated myocardial remodeling and diastolic dysfunction in HFpEF mice through downregulation of the miR-132/Smad3 pathway.