MAP Kinase Kinase Kinase-2 (MEKK2) regulates hypertrophic remodeling of right ventricle in hypoxia-induced pulmonary hypertension.

1University of Colorado Denver.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 11/2012; 304(2). DOI: 10.1152/ajpheart.00158.2012
Source: PubMed


Pulmonary hypertension (PH) results in pressure overload of the right ventricle of the heart, initiating pathological right ventricular remodeling and ultimately leading to right heart failure. Substantial research indicates that signaling through the MAP kinase superfamily mediates pathologic cardiac remodeling. These considerations led us to test the hypothesis that the regulatory protein MAP Kinase Kinase Kinase-2 (MEKK2) contributes to right ventricular hypertrophy in hypoxia-induced pulmonary hypertension. Transgenic mice with global knockout of MEKK2 (MEKK2-/-) and age-matched wild type mice (WT) were exposed to chronic hypobaric hypoxia (10% O(2), 6 wk), and compared with animals under normoxia. Exposure to chronic hypoxia induced PH in WT and MEKK2-/- mice. In response to PH, WT mice showed RV hypertrophy, demonstrated as increased ratio of RV weight:body weight; increased RV wall thickness at diastole, and increased cardiac myocyte size, compared to normoxic control animals. In contrast, each of these measures of RV hypertrophy seen in WT mice following chronic hypoxia was attenuated in MEKK2-/- mice. Furthermore, chronic hypoxia elicits altered programs of hypertrophic and inflammatory gene expression consistent with pathologic RV remodeling in WT mice; MEKK2-/- deletion selectively inhibited inflammatory gene expression compared to WT. The actions of MEKK2 are mediated in part through regulation of the abundance and expression of its effector ERK5. In conclusion, signaling by MEKK2 contributes to right ventricular hypertrophy and altered myocardial inflammatory gene expression in response to hypoxia-induced pulmonary hypertension. Therapies targeting MEKK2 may protect the myocardium from hypertrophy and pathologic remodeling in human pulmonary hypertension.

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Available from: Kurt Stenmark, Dec 28, 2015
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    • "[10]–[22] Although the effect of hypoxia on RV function remains largely unstudied, the few studies that did look at fractional shortening or RV cardiac output failed to show a decrease. [23], [24] However, one must note that this included only short-term exposure to hypoxia. "
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