Abstract 8742: Deletion of CIKS (Act1 or traf3ip2) Abrogates Angiotensin-II-induced Cardiac Hypertrophy in vitro and in vivo
Chronic elevation of Angiotensin-II (Ang-II) can lead to cardiac hypertrophy and heart failure. Ang-II activates NF-κB and AP-1, and induces pro-inflammatory cytokines and pro-growth factors. The adapter molecule CIKS (connection to IKK and SAPK/JNK; also known as Act1 or traf3ip2) lies upstream of IKK and JNK, and mediates both autoimmune and inflammatory diseases. We hypothesized that CIKS plays a causal role in Ang-II-induced cardiac hypertrophy. The heart and body weights were similar in both wild type (WT; C57Bl/6) and CIKS null mice (C57Bl6 background). However, continuous infusion of Ang-II (1.5 μg/kg/min for 7 days; n=8/group) led to cardiac hypertrophy (heart wt/tibial length, 38% increase vs saline, P<0.01) and upregulation of CIKS mRNA (2-fold, P<0.05) and protein (3.1-fold, P<0.01) in WT, but not CIKS null mice (P<0.001 vs WT+Ang-II). Ang-II increased heart rate and systolic blood pressure in both, but levels trended higher in the CIKS null (not significant). Ang-II increased NF-κB and AP-1 DNA binding activities, and induced ANP, cytokine (TNF-α, IL-18), growth factor (WISP1), and MMP (MMP-2, -9, and -14) expression/activity in WT, but not CIKS null mice. Ang-II treatment of adult cardiomyocytes from WT resulted in significant hypertrophy (increased cell surface area and protein without DNA synthesis; both at least P<0.01), PI3K, Akt, p70S6K and ribosomal S6 protein activation, and ANP, TNF-α, IL-18, WISP1, and MMPs expression. Moreover, Ang-II induced CIKS mRNA (at 1 h, 5.1-fold, P<0.001) and protein (at 2 h, 3.78-fold, P<0.01) in a time- and dose-dependent manner. Importantly, CIKS knockdown (lentiviral shRNA) blunted Ang-II induced IKKβ and JNK activities, p65 and c-Jun phosphorylation, and NF-κB and AP-1 DNA binding and reporter gene activities, cytokine, WISP1, and MMPs in WT-cardiomyocytes. These results were recapitulated in CIKS null cardiomyocytes. Our results demonstrate that CIKS plays a critical role in Ang-II-mediated cardiac hypertrophy in vivo and cardiomyocyte hypertrophy in vitro thorough induction of IKK/NF-κB and JNK/AP-1-dependent cytokine, growth factor, and MMP expression. CIKS is a potential therapeutic target in cardiac hypertrophy and congestive heart failure.
- © 2011 by American Heart Association, Inc.