Aerobic exercise-induced up-regulation of HIF-1α ameliorates heart failure by regulating MCT1 and MPC1 expression

Abstract

Background The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. Based on high sensitivity to hypoxia, the failing heart activates cellular metabolic adaptation to balance energy demand by accumulating hypoxia-inducible factor-1α (HIF-1α). Furthermore, monocarboxylic acid transporter protein 1 (MCT1) and mitochondrial pyruvate carrier 1 (MPC1), as key nodes of metabolic adaptation, affect metabolic homeostasis in the failing rat heart. Aerobic exercise training has been demonstrated to be beneficial in slowing the progression of HF by elevating HIF-1α and MCT1 levels, whereas the modulatory effects of exercise on MCT1 and MPC1 in HF (hypoxia) remain elusive. This research aimed to investigate the effects of exercise associated with MCT1 and MPC1 on HF under hypoxia. Methods Rats were randomly divided into four groups: sham sedentary (SHAM), HF sedentary (HF), HF short-term exercise trained (HF-E1) and HF long-term exercise trained (HF-E2). The left anterior descending branch of the coronary artery was ligated to induce HF in rats, and the delaying effect of exercise on HF in rats was evaluated by ventricular ultrasound (ejection fraction, short-axis shortening rate), HE, and Masson staining, etc. The effects of HIF-1α on metabolism, MCT1 and MPC1 proteins expression in hypoxic H9c2 cells were examined using HIF-1α agonist/inhibitor and lentiviral transfection. Results Our results indicate the presence of severe pathological remodelling (as evidenced by deep myocardial fibrosis, increased infarct size and abnormal hypertrophy of the myocardium, etc.) and reduced cardiac function in the failing hearts of rats in the HF group compared to the SHAM group. Treadmill exercise training ameliorated myocardial infarction (MI)-induced cardiac pathological remodelling and improved cardiac function in HF exercise group rats, and significantly increased the expression of HIF-1α (p < 0.01), MCT1 (p < 0.05) and MPC1 (p < 0.05) proteins compared to HF group rats. In addition, pharmacological overexpression of HIF-1α significantly up-regulated the expression of MCT1 (p < 0.001) and MPC1 (p < 0.001) proteins in hypoxic H9c2 cells. Conclusion The data gathered in this study suggest that long-term aerobic exercise training as a non-pharmacological treatment may be effective in slowing down the disease process, improving the pathological phenotype and enhancing cardiac function by activating myocardial HIF-1α and up-regulating the expression of key proteins (MCT1 and MPC1) in HF rats.