MAP Kinase Kinase Kinase-2 (MEKK2) regulates hypertrophic remodeling of right ventricle in hypoxia-induced pulmonary hypertension.
ABSTRACT 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.
SourceAvailable from: Aurélien Pichon
Chapter: Right ventricle and high altitude[Show abstract] [Hide abstract]
ABSTRACT: In high altitude conditions, as hypoxia induces pulmonary vasoconstriction and increase in pulmonary arterial pressure, right ventricular (RV) function will be affected. The right ventricular function may be affected directly by the hypoxic challenge or indirectly through a pressure overload due to changes in the pulmonary circulation. Both animal and human studies seem to show that moderate or transient hypoxia result in adaptive changes in right ventricle that are reversible with re-exposure to normoxic conditions and RV dysfunction is mainly due to mechanical overload from the pulmonary circulation. When hypoxia is more severe or more prolonged, it may directly impact ventricular diastolic or systolic function through mechanisms that remain to be unraveled. Chronic exposure to hypoxia in high-altitude natives suffering from Monge’s disease may lead to important RV hypertrophy, RV failure and overall cardiac failure The adrenergic system may be involved, as well as HIF, PKC or phospholamban. More studies should be encouraged to use recent Doppler techniques for a better understanding of RV systolic and diastolic function in humans exposed to altitude hypoxia including acute, chronic or chronic intermittent hypoxia.The Right Heart, Edited by Sean P. Gaine, Robert Naeije, Andrew John Peacock, 01/2014: chapter Right ventricle and high altitude: pages 117-130; Springer., ISBN: 978-1-4471-2397-2
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ABSTRACT: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2R899X mouse lung and immunohistochemistry for NF-κB p65 in human PAH lung demonstrate that NF-κB is activated in end-stage disease. Acute inflammation or expression of a constitutively active NF-κB elicits a strong suppression of the BMP pathway in mice inversely correlating to activation of NF-κB targets. However, Bmpr2 mutation does not result in NF-κB activation in early disease development as assessed by luciferase reporter mice. Moreover, Bmpr2 mutant mice in which NF-κB activation is genetically blocked develop PH indistinguishable from that without the block. Finally, delivery of a virus causing NF-κB activation strongly exacerbates development of PH in Bmpr2 mutant mice, associated with increased remodeling.05/2014; DOI:10.3390/diseases2020148
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ABSTRACT: Pulmonary hypertension and subsequent right ventricular (RV) failure are associated with high morbidity and mortality. Prognosis is determined by occurrence of RV failure. Currently, adequate treatment for RV failure is lacking. Further research into the molecular basis for the development of RV failure as well as the development of better murine models of RV failure are therefore imperative. We hypothesize that adding a low-copper diet to chronic hypoxia in mice reinforces their individual effect and that the combination of mild pulmonary vascular remodeling and capillary rarefaction, induces RV failure. Six week old mice were subjected to normoxia (N; 21% O2) or hypoxia (H; 10% O2) during a period of 8 weeks and received either a normal diet (Cu+) or a copper depleted diet (Cu-). Cardiac function was assessed by echocardiography and MRI analysis. Here, we characterized a mouse model of chronic hypoxia combined with a copper depleted diet and demonstrate that eight weeks of chronic hypoxia (10%) is sufficient to induce RV hypertrophy and subsequent RV failure. Addition of a low copper diet to hypoxia did not have any further deleterious effects on right ventricular remodeling.PLoS ONE 06/2014; 9(4):e92983. DOI:10.1371/journal.pone.0092983 · 3.53 Impact Factor