CIKS (Act1 or TRAF3IP2) mediates Angiotensin-II-induced Interleukin-18 expression, and Nox2-dependent cardiomyocyte hypertrophy

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• 作者：Anthony J. Valente^a ; Robert A. Clark^a ; Jalahalli M. Siddesha^b ; Ulrich Siebenlist^c ; Bysani Chandrasekar^b ; ^d ; ^{bchandra@tulane.edu}
• 关键词：Act1 ; activator of NF-魏B ; ACM ; adult cardiomyocytes ; ANF ; atrial natriuretic factor ; AP-1 ; activator protein-1 ; AT1 ; angiotensin II type 1 receptor ; ATRAP ; AT1-receptor-associated protein ; ARAP1 ; type 1 Ang II-receptor-associated protein 1 ; C/EBP ; CCAAT/
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：July, 2012
• 卷：53
• 期：1
• 页码：113-124
• 文件大小：1776 K

摘要

Chronic elevation of angiotensin (Ang)-II can lead to myocardial inflammation, hypertrophy and cardiac failure. The adaptor molecule CIKS (connection to IKK and SAPK/JNK) activates the I魏B kinase/nuclear factor (NF)-魏B and JNK/activator protein (AP)-1 pathways in autoimmune and inflammatory diseases. Since Ang-II is a potent activator of NF-魏B and AP-1, we investigated whether CIKS is critical in Ang-II-mediated cardiac hypertrophy. Here we report that Ang-II induced CIKS mRNA and protein expression, CIKS binding to IKK and JNK perhaps functioning as a scaffold protein, CIKS-dependent IKK/NF-魏B and JNK/AP-1 activation, p65 and c-Jun phosphorylation and nuclear translocation, NF-魏B- and AP-1-dependent IL-18 and MMP-9 induction, and hypertrophy of adult cardiomyocytes isolated from WT, but not CIKS-null mice. These results were recapitulated in WT-cardiomyocytes following CIKS knockdown. Infusion of Ang-II for 7 days induced cardiac hypertrophy, increased collagen content, and upregulated CIKS mRNA and protein expression in WT mice, whereas cardiac hypertrophy and collagen deposition were markedly attenuated in the CIKS-null mice, despite a similar increase in systolic blood pressure and DPI-inhibitable superoxide generation in both types of animals. Further, Ang-II-induced IKK/p65 and JNK/c-Jun phosphorylation, NF-魏B and AP-1 activation, and IL-18 and MMP-9 expression were also markedly attenuated in CIKS-null mice. These results demonstrate that CIKS is critical in Ang-II-induced cardiomyocyte hypertrophy and fibrosis, and that CIKS is an important intermediate in Ang-II-induced redox signaling. CIKS is a potential therapeutic target in cardiac hypertrophy, fibrosis, and congestive heart failure.