Cardiac-restricted overexpression of TRAF3 interacting protein 2 (TRAF3IP2) results in spontaneous development of myocardial hypertrophy, fibrosis, and dysfunction

Manjunath Yariswamy, Tadashi Yoshida, Anthony J. Valente, Hemanth Kumar Kandikattu, Siva S V P Sakamuri, Jalahalli M. Siddesha, Sergiy Sukhanov, Zubaida Saifudeen, Lixin Ma, Ulrich Siebenlist, Jason D. Gardner, Bysani Chandrasekar

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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.

Original languageEnglish (US)
Pages (from-to)19425-19436
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number37
DOIs
StatePublished - Sep 9 2016

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Yariswamy, M., Yoshida, T., Valente, A. J., Kandikattu, H. K., Sakamuri, S. S. V. P., Siddesha, J. M., Sukhanov, S., Saifudeen, Z., Ma, L., Siebenlist, U., Gardner, J. D., & Chandrasekar, B. (2016). Cardiac-restricted overexpression of TRAF3 interacting protein 2 (TRAF3IP2) results in spontaneous development of myocardial hypertrophy, fibrosis, and dysfunction. Journal of Biological Chemistry, 291(37), 19425-19436. https://doi.org/10.1074/jbc.M116.724138