title: CIKS (Act1 or TRAF3IP2) mediates Angiotensin-II-induced Interleukin-18 expression, and Nox2-dependent cardiomyocyte hypertrophy.
abstract: 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 IκB kinase/nuclear factor (NF)-κB and JNK/activator protein (AP)-1 pathways in autoimmune and inflammatory diseases. Since Ang-II is a potent activator of NF-κB 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-κB and JNK/AP-1 activation, p65 and c-Jun phosphorylation and nuclear translocation, NF-κB- 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 7days 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-κB 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.
authors.affiliation: Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Robert A
authors.initials: RA
authors.lastname: Clark
authors.forename: Jalahalli M
authors.initials: JM
authors.lastname: Siddesha
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004719:Endomyocardial Fibrosis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D020382:Interleukin-18 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; C515963:Traf3ip2 protein, mouse; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D003094:Collagen; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein