Exercise Mitigates Cardiac Dysfunction Post-MI in Ovariectomized Mice via miR-21/Sox7-Mediated Suppression of Cardiac Fibroblast Activation

Methods

OVX mice were subjected to a 3-week swimming training before MI induction via permanent ligation of left anterior descending artery. Cardiac systolic function was evaluated by echocardiography. Masson, HE, WGA staining, RT-qPCR, and Western blotting were combined to detect the extent of cardiomyocyte hypertrophy, myocardial fibrosis, and apoptosis.

To explore the key exercise-effectors, we detected microRNAs (miR-21, miR-146a, miR-155) in serum samples of elderly post-MI women subsequent to exercise rehabilitation training. miR-21 expression was further investigated in heart sample of OVX plus MI mice. The role of miR-21 in vivo was elucidated through miR-21 knockout mice model and AAV9-mediated miR-21 overexpression mice model. The function of miR-21 in vitro were evaluated in cardiac fibroblasts isolated from OVX mice and treated with TGF-β to induce its activation. miR-21 targets were revealed by microarray analysis and verified by luciferase reporter and functional rescue assays.

Results: Swimming significantly improved cardiac function in OVX mice post-MI, alleviated cardiomyocyte hypertrophy, reduced myocardial fibrosis, and inhibited apoptosis. miR-21 expression was downregulated by exercise training both in heart of OVX mice post-MI and in serum of elderly women after MI. miR-21 knockout mimicked swimming’s cardioprotective effects towards OVX mice post-MI, while miR-21 overexpression abolished these effects.

The overexpression of miR-21 promoted the TGF-β-induced differentiation of cardiac fibroblasts into myofibroblasts and their proliferation, whereas its inhibition blocked TGF-β’s pro-fibrotic role. Microarray analysis and luciferase assays identified Sox7 as a direct miR-21 target, and Sox7 knockdown reversed anti-fibrotic effect of inhibiting miR-21. Conclusion: Swimming protects against post-MI cardiac dysfunction in OVX mice by downregulating myocardial miR-21, thereby upregulating its target gene Sox7 and inhibiting cardiac fibroblast activation. miR-21 and its downstream target Sox7 contributes to cardioprotective effects of swimming, offering a potential target for postmenopausal MI treatment.