Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10814818 | Cellular Signalling | 2015 | 42 Pages |
Abstract
Sustained activation of the Renin-Angiotensin-Aldosterone System (RAAS) contributes to the pathogenesis of heart failure. Aldosterone (Aldo) is known to induce both myocardial hypertrophy and fibrosis through oxidative stress and proinflammatory pathways. Here we have investigated whether Aldo-mediated cardiomycocyte hypertrophy is dependent on TRAF3IP2, an upstream regulator of IKK and JNK. We also investigated whether the pro-mitogenic and pro-migratory effects of Aldo on cardiac fibroblasts are also mediated by TRAF3IP2. Aldo induced both superoxide and hydrogen peroxide in isolated adult mouse cardiomyocytes (CM), and upregulated TRAF3IP2 expression in part via the mineralocorticoid receptor and oxidative stress. Silencing TRAF3IP2 blunted Aldo-induced IKKβ, p65, JNK, and c-Jun activation, IL-18, IL-6 and CT-1 upregulation, and cardiomyocyte hypertrophy. In isolated adult mouse cardiac fibroblasts (CF), Aldo stimulated TRAF3IP2-dependent IL-18 and IL-6 production, CTGF, collagen I and III expression, MMP2 activation, and proliferation and migration. These in vitro results suggest that TRAF3IP2 may play a causal role in Aldo-induced adverse cardiac remodeling in vivo, and identify TRAF3IP2 as a potential therapeutic target in hypertensive heart disease.
Keywords
IL-18 binding proteinAP-1CT-1DPIIκBARBIKKACE-IANFACMGSTgp130eGFPJnkinhibitory kappa BMMPIL-18BPECMBSAc-Jun N-terminal kinaseIκB kinaseMOIbovine serum albuminAldoaldosteroneLOXinterleukinDiphenyleneiodoniumatrial natriuretic factorcardiac fibroblastsLysyl oxidaseExtracellular matrixmatrix metalloproteinaseAngiotensin receptor blockersangiotensin-converting enzyme inhibitoractivator protein-1enhanced green fluorescent proteinmultiplicity of infectioncardiotrophin-1Adult cardiomyocytesglutathione-S-transferaseglycoprotein 130
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Authors
Naveen K. Somanna, Manjunath Yariswamy, Joseph M. Garagliano, Ulrich Siebenlist, Srinivas Mummidi, Anthony J. Valente, Bysani Chandrasekar,