背景:缺血性心脏病的终末期发展为心力衰竭(HF),其特征是心肌细胞缺氧和代谢紊乱。缺氧衰竭的心脏在对缺氧敏感的细胞中触发缺氧诱导因子-1α(HIF-1α)作用,并通过积累HIF-1α来诱导代谢适应。此外,可溶性单羧酸转运蛋白1(MCT1)和线粒体丙酮酸载体1(MPC1),作为代谢适应的关键节点,影响衰竭大鼠心脏的代谢稳态。据报道,由于增强HIF-1α水平以及MCT1表达,有氧运动训练可以延缓HF的进展。而运动对HF(缺氧)中MCT1和MPC1的影响仍然难以捉摸。本研究旨在探讨低氧条件下MCT1和MPC1运动对HF的影响。
方法:实验大鼠模型由四个研究组组成:假支架(SHAM),HF久坐(HF),HF短期运动训练(HF-E1),HF长期运动训练(HF-E2)。HF通过左冠状动脉前降支结扎开始,通过心室超声(射血分数,分数缩短)和组织学染色。HIF-1α对细胞生长的调节作用,通过HIF-1α激活/抑制剂处理和质粒转染评估缺氧H9c2细胞中的MCT1和MPC1蛋白表达。
结果:我们的结果表明存在严重的病理性重塑(深部心肌纤维化证明,梗死面积增加和心肌异常肥大,等。)和与SHAM组相比,HF组大鼠衰竭心脏的心功能降低。跑步机运动训练改善心梗(MI)所致心衰运动组大鼠心脏病理改变和心功能增强,并显著增加HIF-1α的表达(p<0.05),MCT1(p<0.01)和MPC1(p<0.05)蛋白与HF组大鼠相比。此外,在缺氧H9c2细胞中,HIF-1α的药理学抑制显著下调MCT1和MPC1蛋白的表达。这种现象与HIF-1α在基因水平上的敲低一致。
结论:研究结果表明,长期的有氧运动训练,作为一种非药物治疗,足够有效地削弱疾病过程,改善病理表型,并恢复HF大鼠的心功能。这种益处很可能是由于心肌HIF-1α的激活和MCT1和MPC1的上调。
BACKGROUND: The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The hypoxic failing heart triggers hypoxia-inducible factor-1α (HIF-1α) actions in the cells sensitized to hypoxia and induces metabolic adaptation by accumulating HIF-1α. Furthermore, soluble 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 reported to retard the progression of HF due to enhancing HIF-1α levels as well as MCT1 expressions, whereas the effects of exercise on MCT1 and MPC1 in HF (hypoxia) remain elusive. This research aimed to investigate the action of exercise associated with MCT1 and MPC1 on HF under hypoxia.
METHODS: The experimental rat models are composed of four study groups: sham stented (SHAM), HF sedentary (HF), HF short-term exercise trained (HF-E1), HF long-term exercise trained (HF-E2). HF was initiated via left anterior descending coronary artery ligation, the effects of exercise on the progression of HF were analyzed by ventricular ultrasound (ejection fraction, fractional shortening) and histological staining. The regulatory effects of HIF-1α on cell growth, MCT1 and MPC1 protein expression in hypoxic H9c2 cells were evaluated by HIF-1α activatort/inhibitor treatment and plasmid 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 enhanced cardiac function in HF exercise group rats, and significantly increased the expression of HIF-1α (p < 0.05), MCT1 (p < 0.01) and MPC1 (p < 0.05) proteins compared to HF group rats. Moreover, pharmacological inhibition of HIF-1α in hypoxic H9c2 cells dramatically downregulated MCT1 and MPC1 protein expression. This phenomenon is consistent with knockdown of HIF-1α at the gene level.
CONCLUSIONS: The findings propose that long-term aerobic exercise training, as a non- pharmacological treatment, is efficient enough to debilitate the disease process, improve the pathological phenotype, and reinstate cardiac function in HF rats. This benefit is most likely due to activation of myocardial HIF-1α and upregulation of MCT1 and MPC1.