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

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).

Exaggerated Autophagy in Stanford Type A Aortic Dissection: A Transcriptome Pilot Analysis of Human Ascending Aortic Tissues

“…However, the relationship between autophagy and aortic dissection remains controversial. On the one hand, excessive autophagic activation may induce SMC death and phenotype switch in aortic SMCs [ 27 , 29 ]. On the other hand, appropriate activation of autophagy may have a therapeutic effect on aortic aneurysm or dissection [ 30 , 31 ].…”

RNA Modification by m6A Methylation in Cardiovascular Disease

“…To date, researchers have conducted extensive investigations on cardiovascular disease at the genetic and epigenetic levels, and these studies have greatly deepened our understanding of cardiovascular disease [4][5][6][7][8][9][10][11]. Most conventional therapies available for patients with cardiovascular disease involve protein-targeting drugs.…”

“…Before mRNA is translated into protein, it is regulated via various mechanisms at the transcriptional and posttranscriptional levels. N 6 -Methyladenosine (m 6 A) RNA methylation is methylation that occurs in the N 6 -position of adenosine, which is an RNA epigenetic modification that regulates RNA at the posttranscriptional level [12][13][14]. m 6 A RNA methylation regulates not only the splicing and translation but also the stability of RNA [15].…”

“…N 6 -Methyladenosine (m 6 A) RNA methylation is methylation that occurs in the N 6 -position of adenosine, which is an RNA epigenetic modification that regulates RNA at the posttranscriptional level [12][13][14]. m 6 A RNA methylation regulates not only the splicing and translation but also the stability of RNA [15]. Recently, the critical role of m 6 A in cardiovascular diseases has been highlighted [16], and in this review, we summarize the research advances in our understanding of m 6 A-dependent biological functions and molecular mechanisms in cardiovascular disease.…”

“…m 6 A RNA methylation regulates not only the splicing and translation but also the stability of RNA [15]. Recently, the critical role of m 6 A in cardiovascular diseases has been highlighted [16], and in this review, we summarize the research advances in our understanding of m 6 A-dependent biological functions and molecular mechanisms in cardiovascular disease.…”