期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 132, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2020.110897
关键词
Mitochondrial quality control; Tongmai formula; Myocardial ischemia/reperfusion; Mitochondrial morphosis; Mitochondrial dynamics
资金
- National Natural Science Foundation of China [81822047]
- National Key R&D Program of China [2018YFC1704502]
- Fundamental Research Funds for the Central Universities [2019XZZX004-16]
- Tianjin Outstanding Youth Science Foundation [17JCJQJC46200]
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 immunohisto-chemistry 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 (Delta Psi m) 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 Delta Psi m 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.
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