Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction.

Autor:	Yariswamy M; From the Department of Medicine and Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201., Yoshida T; From the Department of Medicine and., Valente AJ; University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229., Kandikattu HK; From the Department of Medicine and., Sakamuri SS; Department of Medicine and., Siddesha JM; Department of Medicine and., Sukhanov S; From the Department of Medicine and., Saifudeen Z; Department of Pediatric Nephrology Tulane University School of Medicine, New Orleans, Louisiana 70112., Ma L; Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201, Department of Radiology, University of Missouri, Columbia, Missouri 65211., Siebenlist U; Laboratory of Molecular Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and., Gardner JD; Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112., Chandrasekar B; From the Department of Medicine and Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201, chandrasekarb@health.missouri.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2016 Sep 09; Vol. 291 (37), pp. 19425-36. Date of Electronic Publication: 2016 Jul 27.
DOI:	10.1074/jbc.M116.724138
Abstrakt:	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. (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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