Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 429, Issue C, Pages 84-92Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2016.03.038
Keywords
RAAS; Aldosterone; TRAF3IP2; CIKS; Act1; Cardiac fibrosis; Cardiac hypertrophy
Categories
Funding
- Department of Veterans Affairs
- VA Office of Research and Development Biomedical Laboratory Research and Development Service [I01-BX002255]
- NIH/NHLBI [HL-86787]
- NHLBI [HL-70241, HL-80682]
- NIH/NIAID
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Aberrant activation of the renin-angiotensin-aldosterone system (RAAS) contributes to adverse cardiac remodeling and eventual failure. Here we investigated whether TRAF3 Interacting Protein 2 (TRAF3IP2), a redox-sensitive cytoplasmic adaptor molecule and an upstream regulator of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), mediates aldosterone-induced cardiac hypertrophy and fibrosis. Wild type (WT) and TRAF3IP2-null mice were infused with aldosterone (0.2 mg/kg/day) for 4 weeks along with 1%NaCl in drinking water. Aldosterone/salt, but not salt alone, upregulated TRAF3IP2 expression in WT mouse hearts. Further, aldosterone elevated blood pressure to a similar extent in both WT and TRAF3IP2-null groups. However, TRAF3IP2 gene deletion attenuated aldosterone/salt-induced (i) p65 and c-Jun activation, (ii) extracellular matrix (collagen I alpha 1 and collagen III alpha 1), matrix metalloproteinase (MMP2), lysyl oxidase (LOX), inflammatory cytokine (IL-6 and IL-18), chemokine (CXCL1 and CXCL2), and adhesion molecule (ICAM1) mRNA expression in hearts, (iii) IL-6, IL-18, and MMP2 protein levels, (iv) systemic IL-6 and IL-18 levels, and (iv) cardiac hypertrophy and fibrosis. These results indicate that TRAF3IP2 is a critical signaling intermediate in aldosterone/salt-induced myocardial hypertrophy and fibrosis, and thus a potential therapeutic target in hypertensive heart disease. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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