EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation
EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation
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EHMT2/G9a 通过抑制自噬激活来抑制主动脉平滑肌细胞死亡
DOI：
10.7150/ijbs.38835
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Jiang, Ding-Sheng
中科院分区：
文献类型：
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作者：
Chen, Tai-Qiang;Hu, Nan;Jiang, Ding-Sheng
虽然EHMT 2（也称为G9 a）在几种癌症和心脏重塑中起着关键作用，但其在血管平滑肌细胞（VSMCs）中的功能仍然未知。在本研究中，我们揭示了一个新的功能，EHMT 2在调节自噬细胞死亡（ACD）的VSMC。BIX 01294抑制EHMT 2或敲低EHMT 2导致VSMC数量减少，这与增殖和凋亡无关。有趣的是，EHMT 2蛋白水平在用自噬诱导剂处理的VSMC中显著降低。此外，在用BIX 01294或lenti-shEHMT 2处理的VSMCs中检测到比其对应物更多的自噬空泡和积累的LC 3 II。此外，我们发现EHMT 2通过抑制自噬体的形成来抑制VSMCs的ACD。从机制上讲，EHMT 2抑制引起的促自噬作用与SQSTM 1和BECN 1过表达相关。此外，这些不利影响在很大程度上被SQSTM 1或BECN 1敲低所抵消。更重要的是，在原代人主动脉VSMC中观察到类似的结果。总的来说，这些发现表明EHMT 2通过降低SQSTM 1或BECN 1表达而作为ACD的关键负调节剂发挥作用，并且EHMT 2可能是心血管疾病的有效治疗靶点（例如，主动脉夹层）。
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).