title: Interleukin-17A mediates cardiomyocyte apoptosis through Stat3-iNOS pathway.
abstract: Interleukin-17A, a pro-inflammatory cytokine, has a direct proapoptotic effect on cardiomyocytes. However, the specific mechanism has not been clarified. In the present study, an in-vitro model of cardiomyocyte apoptosis induced by IL-17A stimulation was employed and the roles of iNOS and Stat3 involved were investigated. Our data showed that the neonatal mouse cardiomyocytes express IL-17 receptors: IL-17RA and IL-17RC, but did not express IL-17A. Exogenous IL-17A significantly induces iNOS expression and hence the cardiomyocyte apoptosis. Moreover, IL-17A-induced cardiomyocyte apoptosis can be achieved directly via iNOS activation. We further showed that exogenous IL-17A simultaneously triggers Stat3 activation, which in turn inhibits IL-17A-induced iNOS expression in cardiomyocytes. And both ChIP and dual-luciferase results confirmed that Stat3 directly inhibits transcriptional activities of iNOS via binding to its specific promoter region. Consistent with these data, silencing of Stat3 in fact can aggravate IL-17A-triggered cardiomyocyte apoptosis. Finally, using an in vivo myocardial ischemia/reperfusion injury model, we verified that Stat3 inhibition increased iNOS expression and exacerbated cardiomyocyte apoptosis. Thus, our data strongly support the notion that Stat3 plays a compensatory anti-apoptotic role in IL-17A/iNOS-mediated cardiomyocyte apoptosis via inhibiting iNOS transcription, providing a novel molecular mechanism of apoptosis regulation and complicated interactions between IL-17A/iNOS and IL-17A/Stat3 signalings.
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China.
authors: Sheng-An
authors: SA
authors: Su
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China.
authors: Du
authors: D
authors: Yang
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China.
authors: Wei
authors: W
authors: Zhu
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China.
authors: Zhejun
authors: Z
authors: Cai
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China.
authors: Na
authors: N
authors: Zhang
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China.
authors: Lina
authors: L
authors: Zhao
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China.
authors: Jian-An
authors: JA
authors: Wang
authors: Cardiovascular Key Lab of Zhejiang Province, Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hang Zhou, Zhejiang 310009, PR China. Electronic address: xiangmx@zju.edu.cn.
authors: Meixiang
authors: M
authors: Xiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Apoptosis; Cardiomyocyte; Interleukin-17A; Ischemia/reperfusion injury; Stat3; iNOS