甲基苯丙胺通过GATA4/NF-κB/SASP轴介导的细胞衰老诱导心肌病。

Methamphetamine induces cardiomyopathy through GATA4/NF-κB/SASP axis-mediated cellular senescence.

作者信息

Zhao Xu, Lu Jiancong, Zhang Cui, Chen Chuanxiang, Zhang Manting, Zhang Jingyi, Du Qingfeng, Wang Huijun

机构信息

Centre of General Practice, The Seventh Affiliated Hospital, Southern Medical University, Foshan 528200, China.

School of Forensic Medicine, Southern Medical University, Guangzhou 510515, China; Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou 510515, China.

出版信息

Toxicol Appl Pharmacol. 2023 May 1;466:116457. doi: 10.1016/j.taap.2023.116457. Epub 2023 Mar 11.

DOI:10.1016/j.taap.2023.116457

PMID:36914120

Abstract

With the world pandemic of methamphetamine (METH), METH-associated cardiomyopathy (MAC) has become a widespread epidemic and is also recognized as a cause of heart failure in young people. The mechanism of occurrence and development of MAC is not clear. In this study, firstly, the animal model was evaluated by echocardiography and myocardial pathological staining. The results revealed that the animal model exhibited cardiac injury consistent with clinical alterations of MAC, and the mice developed cardiac hypertrophy and fibrosis remodeling, which led to systolic dysfunction and left ventricular ejection fraction (%LVEF) < 40%. The expression of cellular senescence marker proteins (p16 and p21) and senescence-associated secretory phenotype (SASP) was significantly increased in mouse myocardial tissue. Secondly, mRNA sequencing analysis of cardiac tissues revealed the key molecule GATA4, and Western blot, qPCR and immunofluorescence results showed that the expression level of GATA4 was significantly increased after METH exposure. Finally, knockdown of GATA4 expression in H9C2 cells in vitro significantly attenuated METH-induced cardiomyocyte senescence. Consequently, METH causes cardiomyopathy through cellular senescence mediated by the GATA4/NF-κB/SASP axis, which is a feasible target for the treatment of MAC.

摘要

随着甲基苯丙胺（METH）在全球范围内的流行，与METH相关的心肌病（MAC）已成为一种广泛传播的流行病，并且也被认为是年轻人心力衰竭的一个原因。MAC发生和发展的机制尚不清楚。在本研究中，首先通过超声心动图和心肌病理染色对动物模型进行评估。结果显示，该动物模型表现出与MAC临床改变一致的心脏损伤，小鼠出现心脏肥大和纤维化重塑，导致收缩功能障碍和左心室射血分数（%LVEF）<40%。小鼠心肌组织中细胞衰老标记蛋白（p16和p21）的表达以及衰老相关分泌表型（SASP）显著增加。其次，对心脏组织进行mRNA测序分析发现了关键分子GATA4，蛋白质免疫印迹、qPCR和免疫荧光结果表明，METH暴露后GATA4的表达水平显著升高。最后，在体外敲低H9C2细胞中GATA4的表达可显著减轻METH诱导的心肌细胞衰老。因此，METH通过GATA4/NF-κB/SASP轴介导的细胞衰老导致心肌病，这是治疗MAC的一个可行靶点。