1. Academic Validation
  2. Tongmai formula improves cardiac function via regulating mitochondrial quality control in the myocardium with ischemia/reperfusion injury

Tongmai formula improves cardiac function via regulating mitochondrial quality control in the myocardium with ischemia/reperfusion injury

  • Biomed Pharmacother. 2020 Dec;132:110897. doi: 10.1016/j.biopha.2020.110897.
Yu Zhao 1 Rui Guo 1 Lan Li 2 Sheng Li 2 Guanwei Fan 2 Xiaoping Zhao 3 Yi Wang 4
Affiliations

Affiliations

  • 1 Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, PR China; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, 300193, PR China.
  • 3 College of Preclinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, PR China. Electronic address: zhaoxiaoping8686@sina.com.
  • 4 Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: zjuwangyi@zju.edu.cn.
Abstract

Background: Mitochondrial quality control, regulated by mitochondrial dynamics and Mitophagy, has been regarded as pivotal process to induce segregation of mitochondria during myocardial ischemia/reperfusion (I/R) injury. However, few works revealed the regulation of mitochondrial quality control by therapeutic agents. Tongmai formula (TM) is a clinically used botanical drug for treating cardiovascular diseases, which mechanism is unveiled. Thus, in this study, we investigated the pharmacological effects of TM on modulating mitochondrial quality control during cardiac injury.

Methods: Rats subjected to myocardial I/R injury and neonatal rat ventricular myocytes (NRVMs) exposed to hypoxia/reoxygenation (H/R) were used to simulate cardiac injury during myocardial ischemia/reperfusion process. Morphological examination, histopathological examination, echocardiography, and immunohistochemistry were used to determine the cardiac injury after I/R injury. Biochemical indices in serum were estimated by the enzyme-linked immunosorbent assays (ELISA). 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1) was used for mitochondrial membrane potential (ΔΨm) evaluation. 2',7'-dichlorofluorescin diacetate (DCFH-DA) was used for intracellular Reactive Oxygen Species (ROS) evaluation. Mitochondria in NRVMs were labeled by tetramethylrhodamine methyl ester (TMRM) for mitochondrial morphosis imaging and estimation. Western blotting was used for cytochrome c (CYCS), Apoptosis inducing factor (AIF) and mitofusin 2 (Mfn2) contents evaluation. Immunochemistry fluorescence was used for Dynamin related protein 1 (Drp1) expression measurement.

Results: TM treatment markedly decreased myocardium infarct size. It also significantly improved left ventricular contractile function and alleviated cardiomyocytes Apoptosis, as well as reduced the production of cardiac troponin T, creatine kinase, Lactate Dehydrogenase, malondialdehyde and elevated glutathione and superoxide dismutase. Intriguingly, we found that mitochondrial membrane potential loss and mitochondrial permeability transition pore (mPTP) opening were recovered after TM treatment. It also down-regulated cytochrome c and Apoptosis inducing factor contents after myocardial I/R injury. In vitro study showed that TM treatment reduced intracellular ROS content and recovered ΔΨm in NRVMs after H/R injury. We also observed that TM could reduce the expression level of Drp1, while increased Mfn2 in NRVMs after H/R injury, which indicates that TM may regulate mitochondrial dynamics during H/R injury of NRVMs.

Conclusions: TM exhibited cardiac protective effect on ischemic myocardium of rats after reperfusion and improved mitochondrial quality control through mitochondrial dynamics in NRVMs after H/R injury.

Keywords

Mitochondrial dynamics; Mitochondrial morphosis; Mitochondrial quality control; Myocardial ischemia/reperfusion; Tongmai formula.

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