Po-Ge-Jiu-Xin decoction alleviate sepsis-induced cardiomyopathy via regulating phosphatase and tensin homolog-induced putative kinase 1 /parkin-mediated mitophagy

ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis is a life-threatening systemic syndrome usually accompanied by myocardial dysfunction. Po-Ge-Jiu-Xin decoction (PGJXD), a traditional Chinese prescription medicine, has been used clinically to treat cardiovascular disease including heart failure, sepsis-induced cardiomyopathy (SIC) and even septic shock. Previous clinical studies suggested PGJXD has shown promising results in improving cardiac function and treating heart failure in sepsis. However, more research is needed to elucidate the mechanisms underlying PGJXD's therapeutic effects in sepsis-induced cardiomyopathy. MATERIALS AND METHODS: Initially, we identified the major compounds of PGJXD through ultra-performance liquid chromatography-mass spectrometry technology analysis. We established in a SIC rat model using cecal ligation and puncture(CLP) and treated by PGJXD and levosimendan. We evaluated pathological damage by hematoxylin and eosin staining and measured serum myocardial injury biomarkers. Myocardial apoptosis was detected by Tunel staining and quantifying specific biomarker protein levels. Subsequently, we evaluated myocardium mitochondrial quality using Transmission electron microscope (TEM), antioxidant stress indexes and tissue adenosine triphosphate(ATP) content. We detected the expression of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), parkin, LC3, and p62 using Western blotting and Quantitative real time polymerase chain reaction(qRT-PCR). (Lipopolysaccharides, LPS)-induced H9c2 cell model was established to further explore the mechanism of PGJXD on SIC. In addition to measuring cell viability, we measured mitochondrial membrane potential using JC-1 staining. Additionally, Parkin-siRNA transfected into H9c2 cells to validate whether PGJXD conducted protective effects against SIC through PINK1/Parkin-mediated mitophagy. RESULTS: It has been demonstrated that PGJXD reduced mortality in septic rat, contributed to ameliorating myocardium injury, suppressed inflammatory response and ameliorated the myocardial apoptosis. PGJXD could also alleviate mitochondrial structural abnormality, mitigated oxidative stress injury and promoted energy synthesis in CLP models. Western blotting and qRT-PCR have further confirmed that PGJXD can activate PINK1/parkin pathway-mediated mitophagy, resulting in preserving mitochondrial quality in the myocardium. Furthermore, Parkin siRNA partially reversed the beneficial effect of PGJXD on mitochondrial fission/fusion and mitophagy in vitro. Therefore, the cardioprotective effect of PGJXD is achieved by inducing PINK1/Parkin-mediated mitophagy in maintaining mitochondrial homeostasis. CONCLUSIONS: These results suggest that the potential therapeutic effect of PGJXD on cardiac dysfunction during sepsis and support its mechanism of targeted induction of PINK1-Parkin-mediated mitophagy.