title: TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis.
abstract: 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-κB (NF-κB) 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 Iα1 and collagen IIIα1), 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.
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
authors.forename: Siva S V P
authors.initials: SS
authors.lastname: Sakamuri
authors.affiliation: Medicine, University of Texas Health Science Center, San Antonio, TX 78229, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
authors.forename: Jalahalli M
authors.initials: JM
authors.lastname: Siddesha
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.affiliation: Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, MD 20892, United States.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gardner
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States. Electronic address: chandrasekarb@health.missouri.edu.
authors.forename: Chandrasekar
authors.initials: C
authors.lastname: Bysani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000450:Aldosterone / Q000009:adverse effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012965:Sodium Chloride; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; C515963:Traf3ip2 protein, mouse; D018808:Transcription Factor AP-1; D012965:Sodium Chloride; D000450:Aldosterone; D020778:Matrix Metalloproteinase 2
keywords: Act1; Aldosterone; CIKS; Cardiac fibrosis; Cardiac hypertrophy; RAAS; TRAF3IP2