Int J Biol Sci 2020; 16(7):1252-1263. doi:10.7150/ijbs.38835

Research Paper

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Tai-Qiang Chen1*, Nan Hu2*, Bo Huo1, Jackson Ferdinand Masau1, Xin Yi3, Xiao-Xuan Zhong1, Yong-Jie Chen1, Xian Guo1, Xue-Hai Zhu1,4,5,6, Xiang Wei1,4,5,6✉, Ding-Sheng Jiang1,4,5,6✉

1. Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
2. Department of Cardiothoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China;
3. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China;
4. Key Laboratory of Organ Transplantation, Ministry of Education;
5. NHC Key Laboratory of Organ Transplantation;
6. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences
*These authors contributed equally to this work

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Citation:
Chen TQ, Hu N, Huo B, Masau JF, Yi X, Zhong XX, Chen YJ, Guo X, Zhu XH, Wei X, Jiang DS. EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation. Int J Biol Sci 2020; 16(7):1252-1263. doi:10.7150/ijbs.38835. Available from http://www.ijbs.com/v16p1252.htm

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Abstract

Although EHMT2 (also known as G9a) plays a critical role in several kinds of cancers and cardiac remodeling, its function in vascular smooth muscle cells (VSMCs) remains unknown. In the present study, we revealed a novel function of EHMT2 in regulating autophagic cell death (ACD) of VSMC. Inhibition of EHMT2 by BIX01294 or knockdown of EHMT2 resulted in reduced VSMC numbers which were independent of proliferation and apoptosis. Interestingly, EHMT2 protein levels were significantly decreased in VSMCs treated with autophagic inducers. Moreover, more autophagic vacuoles and accumulated LC3II were detected in VSMCs treated with BIX01294 or lenti-shEHMT2 than their counterparts. Furthermore, we found that EHMT2 inhibited the ACD of VSMCs by suppressing autophagosome formation. Mechanistically, the pro-autophagic effect elicited by EHMT2 inhibition was associated with SQSTM1 and BECN1 overexpression. Moreover, these detrimental effects were largely nullified by SQSTM1 or BECN1 knockdown. More importantly, similar results were observed in primary human aortic VSMCs. Overall, these findings suggest that EHMT2 functions as a crucial negative regulator of ACD via decreasing SQSTM1 or BECN1 expression and that EHMT2 could be a potent therapeutic target for cardiovascular diseases (e.g., aortic dissection).

Keywords: EHMT2/G9a, Vascular smooth muscle cells, Autophagy, SQSTM1, BECN1