Mzb1 protects against myocardial infarction injury in mice via modulating mitochondrial function and alleviating inflammation

Authors: Lu Zhang1,2, Yi-ning Wang1,2, Jia-ming Ju2, Azaliia Shabanova1,2,3, Yue Li1,2, Ruo-nan Fang1,2, Jia-bin Sun1,2, Ying-ying Guo1,2, Tong-zhu Jin1,2, Yan-yan Liu1,2, Tian-yu Li1,2, Hong-li Shan1,2,4, Hai-hai Liang1,2,4, Bao-feng Yang1,2,4
1 Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
2 Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150081, China
3 Department of Outpatient and Emergency Pediatric, Bashkir State Medical University, Ground Floor, Teatralnaya Street, 2a, 450000 Ufa, Russia
4 Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
Correspondence to: Hai-hai Liang:, Bao-feng Yang:,
DOI: 10.1038/s41401-020-0489-0
Received: 16 April 2020
Accepted: 20 July 2020
Advance online: 5 August 2020


Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle dilation and cardiac dysfunction, eventually developing into heart failure. Mzb1 (Marginal zone B and B1 cell specific protein 1) is a B-cell-specific and endoplasmic reticulum-localized protein. Mzb1 is an inflammation-associated factor that participates a series of inflammatory processes, including chronic periodontitis and several cancers. In this study we investigated the role of Mzb1 in experimental models of MI. MI was induced in mice by ligation of the left descending anterior coronary artery, and in neonatal mouse ventricular cardiomyocytes (NMVCs) by H2O2 treatment in vitro. We showed that Mzb1 expression was markedly reduced in the border zone of the infarct myocardium of MI mice and in H2O2-treated NMVCs. In H2O2-treated cardiomyocytes, knockdown of Mzb1 decreased mitochondrial membrane potential, impaired mitochondrial function and promoted apoptosis. On contrary, overexpression of Mzb1 improved mitochondrial membrane potential, ATP levels and mitochondrial oxygen consumption rate (OCR), and inhibited apoptosis. Direct injection of lentiviral vector carrying Len-Mzb1 into the myocardial tissue significantly improved cardiac function and alleviated apoptosis in MI mice. We showed that Mzb1 overexpression significantly decreased the levels of Bax/Bcl-2 and cytochrome c and improved mitochondrial function in MI mice via activating the AMPK-PGC1α pathway. In addition, we demonstrated that Mzb1 recruited the macrophages and alleviated inflammation in MI mice. We conclude that Mzb1 is a crucial regulator of cardiomyocytes after MI by improving mitochondrial function and reducing inflammatory signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy.
Keywords: myocardial infarction; cardiomyocyte; Mzb1; mitochondria; inflammation; apoptosis; AMPK-PGC1α pathway; macrophages

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