Upregulation of sestrin-2 expression protects against endothelial toxicity of angiotensin II.
Sestrin-2 (SESN2) is involved in the cellular response to different stress conditions. However, the function of SESN2 in the cardiovascular system remains unknown. In the present study, we tested whether SESN2 has a beneficial effect on vascular endothelial damage induced by angiotensin II (AngII). Firstly, we found that AngII induces expression of SESN2 in human umbilical vein endothelial cells (HUVECs) in a time-dependent and dose-dependent manner. We also found that knockdown of SESN2 using small RNA interference promotes cellular toxicity of AngII, as well as a reduction in cell viability, exacerbation of oxidative stress, and stimulation of apoptosis. In addition, our results show that the c-Jun NH (2)-terminal kinase (JNK)/c-Jun pathway is activated by AngII. Inhibiting the activity of the JNK pathway abolishes the increase in SESN2 induced by AngII. Importantly, overexpression of c-Jun promotes luciferase activity of the SESN2 promoter. These findings suggest that the inductive effect of SESN2 is mediated by the JNK/c-Jun pathway. Our results indicate that the induction of SESN2 acts as a compensatory response to AngII for survival, implying that stimulating expression of SESN2 might be an effective pharmacological target for the treatment of AngII-associated cardiovascular diseases.
Department of Cardiology, Zhong Shan Hospital at Sun Yat-Sen University, No. 2 Sun Wendong Road, Zhongshan City, Guangdong Province, 528403, China.
Lao
L
Yi
Feng
F
Li
Yuan
Y
Yong
Dong
D
Jianting
Zhang
Z
Liting
Huang
H
Xuansheng
Li
L
Fei
Li
L
Jiewen
D000447:Aldehydes / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D000084622:Sestrins
D000447:Aldehydes; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D007770:L-Lactate Dehydrogenase; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; C465398:SESN2 protein, human; D000084622:Sestrins; C027576:4-hydroxy-2-nonenal