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.
"– 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. ,  However, one must note that this included only short-term exposure to hypoxia. "
[Show abstract][Hide abstract] 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 · 3.23 Impact Factor
[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
[Show abstract][Hide abstract] ABSTRACT: The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RAGE) have recently been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodelling in experimental pulmonary arterial hypertension (PH). Here, the effects of RAGE antagonism upon 2 weeks of hypobaric hypoxia (10% O2)-induced PH in mice were assessed. Treatment with sRAGE was protective against hypobaric hypoxia-induced increases in right ventricular pressure but distal pulmonary vascular remodelling was unaffected. Intralobar pulmonary arteries from hypobaric hypoxic mice treated with sRAGE showed protection against a hypoxia-induced reduction in compliance. However, a combination of sRAGE and hypoxia also dramatically increased the force of contractions to KCl and 5-HT observed in these vessels. The acute addition of sRAGE to the organ bath produced a small, sustained contraction in intralobar pulmonary vessels and produced a synergistic enhancement of the maximal force of contraction in subsequent concentration-response curves to 5-HT. sRAGE had no effect on 5-HT-induced proliferation of Chinese hamster lung fibroblasts (CCL39), used since they have a similar pharmacological profile to mouse pulmonary fibroblasts but, surprisingly, produced a marked increase in hypoxia-induced proliferation. These data implicate RAGE as a modulator of both vasoreactivity and of proliferative processes in the response of the pulmonary circulation to chronic-hypoxia.
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