Background: Mitochondrial dysfunction has been implicated in the pathogenesis of ischemic heart disease, exacerbating cardiomyocytes injury in myocardial infarction (MI). Peroxisome proliferator-activated receptor gamma co-activator (PGC-1α) has been recognized as the key regulator of mitochondrial biogenesis and energy metabolism. Yiqihuoxue decoction (YQHX), a Traditional Chinese Medicine (TCM) prescription, can prevent and treat ischemic heart disease. However, the mechanisms of YQHX on PGC-1α expression in the ischemic heart have remained unclear.
Methods: Myocardial ischemia rat model and ischemia/hypoxia injury model in the cardiomyocytes were used to minic human cardiovascular disease. Rats were randomly assigned into 4 groups: Sham, Model, YQHX (8.2 g/kg) and Trimetazidine (10 mg/kg) group. 28 days after MI, cardiac functions and morphology were detected by echocardiography and HE staining, respectively. In vitro, the effects of YQHX on H9c2 cell viability, LDH and ROS were detected, respectively. PGC-1α relevant proteins were evaluated by Western blotting.
Results: In vivo, echocardiography and HE staining results showed that YQHX improved cardiac functions and modified pathological changes. YQHX enhanced PGC-1α expression and improved the mitochondrial ultrastructure and functions in rats MI model for 4 weeks. Further, we explored its potential mechanisms in cardiomyocytes. In vitro, YQHX significantly enhanced cell viability and reduced LDH release and ROS production induced by hypoxia in cardiomyocytes. Interestingly, exposure of cardiomyocytes to hypoxic conditions for 12 h induced the downregulation of PGC-1α expression, but the expression levels nearly returned to the normal state after hypoxia for 24 h. YQHX significantly enhanced PGC-1α expression between 12 h and 24 h induced by hypoxia through a mechanism associated with the activation of AMPK phosphorylation in H9c2 cells. In addition, YQHX upregulated the expression of Tfam and NRF-1, while NRF-1 expression was completely blocked by an AMPK inhibitor. YQHX largely restored the mitochondrial morphology and increased mitochondrial membrane potential in hypoxia-induced injury. Furthermore, the UHPLC-LTQ-Orbitrap-MSn analysis found that there were 87 chemical constituents in YQHX.
Conclusions: These results suggest that the protective effect of YQHX on cardiomyocytes against hypoxia-induced injury may be attributed to activation of PGC-1α and maintenance of mitochondrial functions through a mechanism involving the activation of AMPK phosphorylation.
Keywords: Cardiomyocytes; Myocardial ischemia; PGC-1α; Yiqihuoxue decoction (YQHX).