有氧运动通过PPARα/FGF21通路抑制心梗后心室重塑的机制研究

病理性心室重塑是影响心梗患者康复的重要难题。既往研究显示有氧运动可抑制心梗后心室重塑，但具体机制尚不清楚。我们前期研究发现：有氧运动增加心梗小鼠心肌PPARα表达、抑制炎症及改善心功能，而诱导型心肌细胞特异性PPARα敲除小鼠（PparaΔCM）制成心梗小鼠模型，有氧运动未见上述作用。PPARα激动剂增加体外培养心肌细胞FGF21表达、抑制炎症通路，而敲低FGF21表达可逆转上述表现。据此我们假设：有氧运动通过上调心肌细胞PPARα表达、促进FGF21/FGFR1/β-Klotho信号通路激活，进而降低心梗后炎症，从而抑制病理性心室重塑及促进心梗后康复。本项目拟在细胞、动物及人群不同层面，应用PPARα激动剂、慢病毒敲低FGF21/FGFR1/β-Klotho、PparaΔCM转基因小鼠等技术，探讨有氧运动抑制心梗后心室重塑具体机制。为预防及治疗心梗后病理性心室重塑提供新的思路和理论依据。

Pathological ventricular remodeling is responsible for the development of cardiac dysfunction in patients with acute myocardial infarction (AMI). Increasing evidence indicated that aerobic exercise attenuated ventricular remodeling in AMI patients and animal models, but the mechanism remains unclear. Our previous studies showed that aerobic exercise increased the expression of peroxisome proliferator-activated receptor α (PPARα), attenuated inflammation and partially reversed ventricular remodeling and functional damage in AMI mice, but the beneficial effects disappeared in cardiomyocyte -specific PPARα knockout mice. PPARα agonist increased the expression of fibroblast growth factor 21 (FGF21) and inhibited inflammation in cultured cardiomyocytes, while these changes were partly reversed by FGF21 knockout. Based on the findings, we hypothesize that aerobic exercise inhibits the activation of inflammatory pathways and reverses ventricular remodeling following AMI in a PPARα/FGF21 dependent pathway. This study firstly uses AMI patients, coronary artery ligation-induced AMI mice and cardiomyocyte-specific PPARα knockout mice to confirm the effect of aerobic exercise on the PPARα/FGF21 pathway and ventricular remodeling; secondly, by using PPAR agonist/ antagonist or gene manipulation, we explore whether aerobic exercise inhibits the activation of inflammatory pathways and reverses ventricular remodeling following AMI in a PPARα/FGF21 dependent pathway. The study findings will provide new ideas for the prevention and treatment of AMI-induced ventricular remodeling and functional damage.