title: Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2.
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.
authors.affiliation: Department of Microbiology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Somanna
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA.
authors.forename: Manjunath
authors.initials: M
authors.lastname: Yariswamy
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Garagliano
authors.affiliation: University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, MD 20892, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mummidi
authors.affiliation: Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, MD 20892, USA.
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, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA; University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D006984:Hypertrophy / Q000378:metabolism; D020382:Interleukin-18 / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000502:physiology*; D010084:Oxidation-Reduction; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology*; D020257:Ventricular Remodeling
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020382:Interleukin-18; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D050822:Cytokine Receptor gp130; D000450:Aldosterone; D008249:Protein-Lysine 6-Oxidase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Aldosterone; Hypertrophy; Migration; Mitogenesis; RAAS; TRAF3IP2