title: Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction.
abstract: TRAF3IP2 (TRAF3 interacting protein 2; previously known as CIKS or Act1) is a key intermediate in the normal inflammatory response and the pathogenesis of various autoimmune and inflammatory diseases. Induction of TRAF3IP2 activates IκB kinase (IKK)/NF-κB, JNK/AP-1, and c/EBPβ and stimulates the expression of various inflammatory mediators with negative myocardial inotropic effects. To investigate the role of TRAF3IP2 in heart disease, we generated a transgenic mouse model with cardiomyocyte-specific TRAF3IP2 overexpression (TRAF3IP2-Tg). Echocardiography, magnetic resonance imaging, and pressure-volume conductance catheterization revealed impaired cardiac function in 2-month-old male transgenic (Tg) mice as evidenced by decreased ejection fraction, stroke volume, cardiac output, and peak ejection rate. Moreover, the male Tg mice spontaneously developed myocardial hypertrophy (increased heart/body weight ratio, cardiomyocyte cross-sectional area, GATA4 induction, and fetal gene re-expression). Furthermore, TRAF3IP2 overexpression resulted in the activation of IKK/NF-κB, JNK/AP-1, c/EBPβ, and p38 MAPK and induction of proinflammatory cytokines, chemokines, and extracellular matrix proteins in the heart. Although myocardial hypertrophy decreased with age, cardiac fibrosis (increased number of myofibroblasts and enhanced expression and deposition of fibrillar collagens) increased progressively. Despite these adverse changes, TRAF3IP2 overexpression did not result in cell death at any time period. Interestingly, despite increased mRNA expression, TRAF3IP2 protein levels and activation of its downstream signaling intermediates remained unchanged in the hearts of female Tg mice. The female Tg mice also failed to develop myocardial hypertrophy. In summary, these results demonstrate that overexpression of TRAF3IP2 in male mice is sufficient to induce myocardial hypertrophy, cardiac fibrosis, and contractile dysfunction.
authors.affiliation: From the Department of Medicine and Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201.
authors.forename: Manjunath
authors.identifier: 0000-0003-1833-6998
authors.initials: M
authors.lastname: Yariswamy
authors.affiliation: From the Department of Medicine and.
authors.forename: Tadashi
authors.identifier: 0000-0002-4544-1497
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: Anthony J
authors.identifier: 0000-0002-2172-3166
authors.initials: AJ
authors.lastname: Valente
authors.affiliation: From the Department of Medicine and.
authors.forename: Hemanth Kumar
authors.identifier: 0000-0001-5114-3341
authors.initials: HK
authors.lastname: Kandikattu
authors.affiliation: Department of Medicine and.
authors.forename: Siva S V P
authors.initials: SS
authors.lastname: Sakamuri
authors.affiliation: Department of Medicine and.
authors.forename: Jalahalli M
authors.initials: JM
authors.lastname: Siddesha
authors.affiliation: From the Department of Medicine and.
authors.forename: Sergiy
authors.identifier: 0000-0003-0795-5945
authors.initials: S
authors.lastname: Sukhanov
authors.affiliation: Department of Pediatric Nephrology Tulane University School of Medicine, New Orleans, Louisiana 70112.
authors.forename: Zubaida
authors.initials: Z
authors.lastname: Saifudeen
authors.affiliation: Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201, Department of Radiology, University of Missouri, Columbia, Missouri 65211.
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Laboratory of Molecular Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gardner
authors.affiliation: From the Department of Medicine and Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201, chandrasekarb@health.missouri.edu.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D013318:Stroke Volume; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D018925:Chemokines; D016328:NF-kappa B; C515963:Traf3ip2 protein, mouse; D018808:Transcription Factor AP-1; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: adaptor protein; cardiac hypertrophy; extracellular matrix; fibrosis; heart failure