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.
Highlights
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
Cardiac-restricted TRAF3IP2 Overexpression Results in IKK/ nuclear factor B (NF-B), Jun N-terminal kinase (JNK)/activator protein 1 (AP-1), c/EBP, and p38 MAPK Activation— Because TRAF3IP2 is an upstream regulator of IKK/NF-B, JNK/AP-1, and c/EBP [11, 12, 19], we investigated whether TRAF3IP2 overexpression results in their spontaneous activation
Cardiac-restricted TRAF3IP2 Overexpression Results in Spontaneous Development of Myocardial Hypertrophy and Contractile Dysfunction—Because activation of NF-B, AP-1, c/EBP, and p38 MAPK has been shown to contribute to hypertrophy development [5, 7,8,9,10, 20, 21], we investigated whether TRAF3IP2 overexpression results in myocardial hypertrophy
Summary
Characterization of TRAF3IP2-Tg Mice—We have generated a transgenic mouse model that overexpresses TRAF3IP2 in a cardiomyocyte-specific manner using the ␣-myosin heavy chain (␣-MyHC) promoter (TRAF3IP2-Tg, Fig. 1). End diastolic pressure, end systolic pressure, end diastolic volume, and end systolic volume did not vary between the two groups (Table 1) Together, these data demonstrate that male Tg mice with constitutive overexpression of TRAF3IP2 in a cardiomyocyte-specific manner spontaneously develop myocardial hypertrophy and contractile dysfunction. Anatomic and functional changes in 2-month-old TRAF3IP2-Tg and control NTg littermates n, number of mice; LVID;d, LV internal diameter in diastole; LVID;s, LV internal diameter in systole; LVAW;d, LV anterior wall diameter in diastole; LVPW;d, LV posterior wall diameter at diastole; ESV, end systolic volume; EDV, end diastolic volume; LVEDV, LV end diastolic volume; LVESV, LV end systolic volume; EDP, end diastolic pressure; ESP, end systolic pressure; CO, cardiac output; IFR, initial filling rate; PER, peak ejection rate; PFR, peak filling rate; SV, stroke volume. Results represent the mean Ϯ S.E., and are considered statistically significant if p Ͻ 0.05
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