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Danqi Pill Protects Against Heart Failure Post-Acute Myocardial Infarction via HIF-1?/PGC-1? Mediated Glucose Metabolism Pathway.

ABSTRACT: Aim:Heart failure (HF) post-acute myocardial infarction (AMI) leads to a large number of hospitalizations and deaths worldwide. Danqi pill (DQP) is included in the 2015 national pharmacopoeia and widely applied in the treatment of HF in clinics in China. We examined whether DQP acted on glucose metabolism to protect against HF post-AMI via hypoxia inducible factor-1 alpha (HIF-1?)/peroxisome proliferator-activated receptor ? co-activator (PGC-1?) pathway. Methods and Results:In this study, left anterior descending (LAD) artery ligation induced HF post-AMI rats and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 cell model were structured to explore the efficacy and mechanism of DQP. Here we showed that DQP protected the heart against ischemic damage as evidenced by improved cardiac functions and attenuated inflammatory infiltration. The expressions of critical proteins involved in glucose intake and transportation such as GLUT4 and PKM2 were up-regulated, while negative regulatory proteins involved in oxidative phosphorylation were attenuated in the treatment of DQP. Moreover, DQP up-regulated NRF1 and TFAM, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate (ATP) level. The protection effects of DQP were significantly compromised by HIF-1? siRNA, suggesting that HIF-1? signaling pathway was the potential target of DQP on HF post-AMI. Conclusions:DQP exhibits the efficacy to improve myocardial glucose metabolism, mitochondrial oxidative phosphorylation and biogenesis by regulating HIF-1?/PGC-1? signaling pathway in HF post-AMI rats.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC7187888 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Danqi Pill Protects Against Heart Failure Post-Acute Myocardial Infarction <i>via</i> HIF-1α/PGC-1α Mediated Glucose Metabolism Pathway.

Zhang Qian Q Guo Dongqing D Wang Yuanyuan Y Wang Xiaoping X Wang Qiyan Q Wu Yan Y Li Chun C Wang Wei W Wang Yong Y

Frontiers in pharmacology 20200421

<h4>Aim</h4>Heart failure (HF) post-acute myocardial infarction (AMI) leads to a large number of hospitalizations and deaths worldwide. Danqi pill (DQP) is included in the 2015 national pharmacopoeia and widely applied in the treatment of HF in clinics in China. We examined whether DQP acted on glucose metabolism to protect against HF post-AMI <i>via</i> hypoxia inducible factor-1 alpha (HIF-1α)/peroxisome proliferator-activated receptor α co-activator (PGC-1α) pathway.<h4>Methods and results</h ...[more]

PMID: 32372956

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Project description:BackgroundMitochondrial 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-1?) 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-1? expression in the ischemic heart have remained unclear.MethodsMyocardial 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-1? relevant proteins were evaluated by Western blotting.ResultsIn vivo, echocardiography and HE staining results showed that YQHX improved cardiac functions and modified pathological changes. YQHX enhanced PGC-1? 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-1? expression, but the expression levels nearly returned to the normal state after hypoxia for 24 h. YQHX significantly enhanced PGC-1? 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.ConclusionsThese results suggest that the protective effect of YQHX on cardiomyocytes against hypoxia-induced injury may be attributed to activation of PGC-1? and maintenance of mitochondrial functions through a mechanism involving the activation of AMPK phosphorylation.

Project description:BACKGROUND: Chinese herbal formulae are composed of complex components and produce comprehensive pharmacological effects. Unlike chemical drugs that have only one clear single target, the components of Chinese herbal formulae have multiple channels and targets. How to discover the pharmacological targets of Chinese herbal formulae and their underlying molecular mechanism are still under investigation. METHODS: DanQi pill (DQP), which is one of the widely prescribed traditional Chinese medicines, is applied as an example drug. In this study, we used the drug target prediction model (DrugCIPHER-CS) to examine the underlying molecular mechanism of DQP, followed by experimental validation. RESULTS: A novel therapeutic effect pattern of DQP was identified. After determining the compounds in DQP, we used DrugCIPHER-CS to predict their potential targets. These potential targets were significantly enriched in well-known cardiovascular disease-related pathways. For example, the biological processes of neuroactive ligand-receptor interaction, calcium-signaling pathway, and aminoacyl-tRNA biosynthesis were involved. A new and significant pathway, arachidonic acid (AA) metabolism, was also identified in this study. This predicted pathway alteration was validated with an animal model of heart failure (HF). Results show that DQP had effect both on thromboxane B2 (TXB2) and Prostaglandin I2 (PGI2) in different patterns. It can down-regulate the TXB2 and up-regulate the PGI2 in diverse way. Remarkably, it also had effect on cyclooxygenase (COX)-1 and COX2 by suppressing their levels, which may be the critical and novel mechanism of cardiacprotective efficacy for DQP. Furthermore, leukotrienes B4 (LTB4) receptor, another key molecule of AA metabolism which finally mediated gastrotoxic leukotrienes, was also reduced by DQP. CONCLUSIONS: The combination of drug target prediction and experimental validation provides new insights into the complicated mechanism of DQP.

Dataset Information

Danqi Pill Protects Against Heart Failure Post-Acute Myocardial Infarction via HIF-1?/PGC-1? Mediated Glucose Metabolism Pathway.

Publications

Danqi Pill Protects Against Heart Failure Post-Acute Myocardial Infarction <i>via</i> HIF-1α/PGC-1α Mediated Glucose Metabolism Pathway.

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