Zishen Huoxue decoction (ZSHX) enhances cardiomyocyte viability following hypoxic stress; however, its upstream therapeutic targets remain unclear. Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway. In vitro, ZSHX inhibited pathological mitochondrial fission following hypoxic stress, regulated FUN14 domain-containing protein 1 (FUNDC1)-related mitophagy, and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II (LC3II)/translocase of outer mitochondrial membrane 20 (TOM20) expression while inhibiting the over-activated mitochondrial unfolded protein response. Additionally, ZSHX regulated the stability of beta-tubulin through Sirtuin 5 (SIRT5) and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria (UPR^mt) via the SIRT5 and -β-tubulin axis. This targeting pathway may be crucial for cardiomyocytes to resist hypoxia. Collectively, these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis, which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPR^mt on cardiomyocytes.
Mitophagy/drug effects* ; Tubulin/genetics* ; Animals ; Myocytes, Cardiac/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Sirtuins/genetics* ; Unfolded Protein Response/drug effects* ; Myocardial Ischemia/genetics* ; Rats ; Humans ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Male

Objective To discuss the feasibility of establishing the model of combining myocardial ischemic coronary disease with syndrome of kidney deficiency and blood stasis by surgical method.Methods Non-disease of kidney deficiency and blood stasis syndrome model was built by taking the methods of fright, being placed in a cold environment and injection of hydrocortisone. The model of combining the myocardial ischemic coronary disease with the syndrome of kidney deficiency and blood stasis was established through ligating the left anterior descending branch of artery and injecting hydrocortisone. The rats were divided into kidney deficiency and blood stasis group, combination of disease and syndrome group, and normal group, 5 rats in each group. The temperature, weight, heart rate, breathing rate and whole blood viscosity, casson viscosity of the rats in the two groups before and after modeling were observed. According to TCM clinical diagnosis criteria of kidney deficiency and blood stasis syndrome, TCM syndrome characteristics of the two groups were compared.ResultsCompared with normal groups and before modeling, rat temperature dropped and breathing rate increased in kidney deficiency and blood stasis group, combination of disease and syndrome group (P<0.05). Compared with normal group, rat weight decreased or grew slowly, and whole blood viscosity and casson viscosity increased (P<0.05, P<0.01). There were statistical significant differences in whole blood viscosity and electrocardiogram between the two groups (P<0.05).Conclusion There is no obvious difference between TCM syndrome characteristics of the two groups. They all meet the TCM clinical diagnosis criteria of kidney deficiency and blood stasis syndrome.