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.
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ABSTRACT: Smooth muscle in the pulmonary artery of PAH subjects, both idiopathic and hereditary, is characterized by hyperplasia. Smooth muscle cells (HPASMC) isolated from subjects with or without PAH retain their in vivo phenotype as illustrated by their expression of alpha-smooth muscle actin and expression of H-caldesmon. Both non PAH and PAH HPASMC display a lengthy, approximately 94h, cell cycle. The HPASMC from both idiopathic and hereditary PAH display an abnormal proliferation characterized by continued growth under non-proliferative, non-growth stimulated conditions. This effector independent proliferation is JNK and p38 MAP kinase dependent. Blocking the activation of either abrogates the HPASMC growth. HPASMC from non PAH donors under quiescent conditions display negligible proliferation but divide upon exposure to growth factors such as PDGF-BB or FGF2 but not EGF. This growth does not involve the MAP kinases. Instead it routes via the tyrosine kinase receptor through mTOR and then 6SK. In the PAH cells PDGF-BB and FGF2 augment the dysregulated cell proliferation, also through mTOR/6SK. Additionally, blocking the activation of mTOR also modulates the MAP kinase promoted dysregulated growth. These results highlight key alterations in the growth of HPASMC from subjects with PAH which contribute to the etiology of the disease and can clearly be targeted at various regulatory points for future therapies.PLoS ONE 04/2015; 10(4):e0123662. DOI:10.1371/journal.pone.0123662 · 3.53 Impact Factor
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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
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ABSTRACT: In mammalian cells, responses to hypoxia at the molecular transduction level are hallmarks of adaptation and survival under oxygen deprivation conditions. In this study, the protein expression patterns of mitogen-activated protein kinases (MAPKs) are investigated under hypoxia in primary cortical neurons and in a model of organotypic hippocampal slices in neonatal Sprague-Dawley rats. Abrupt fluctuations in MAPK expression can occur during anoxia, hypoxia, and relative hyperoxic shifts (e.g., reoxygenation); therefore, phosphorylation and dephosphorylation states could be crucial factors in metabolic reorganization for withstanding anaerobiosis. Whole cellular protein extracts were analyzed for the phosphorylation of MAPKp(p38) and MAPK(ERK-1/2 (p44/p42)) at threonine and tyrosine residues (Thr(180)/Tyr(182)) at different time periods of hypoxic exposure relative to a fixed normoxia control. The phospho-MAPK(p38) (p-MAPK(p38)) to MAPK(p38) relative unit ratio revealed that MAPK(p38) expression increased in cortical neurons after 5 and 10 min, but decreased abruptly afterwards (20 - 120 min). The expression of phospho-MAPK(ERK-1) (p-MAPK(ERK-1/p44)), however, decreased whereas that of p-MAPK(ERK-2/p42) increased compared to normoxia. In rat hippocampal slices (RHS), the expression of p-MAPK(p38) was slightly but significantly higher in hypoxia, whereas the expression of p-MAPK(ERK-2/p42) increased and that of p-MAPK(ERK-1/p44) was intangible. This indicates that in cortical neurons hypoxia differentially upregulated the phosphorylation activation states of MAPK(p38) and MAPK(ERK-1/2 (p44/p42)), whereas in the RHS model MAPK(p38) and MAPK(ERK-2/p42), but not MAPK(ERK-1/p44), phosphorylation states were upregulated in response to hypoxia. The neuroimmunological molecular patterns of the differential MAPK phosphorylation in vitro and ex vivo in response to hypoxic shift indicated a significant role for these kinases in cellular adaptation to oxygen deprivation, and thereby may identify physiologic and neuroprotective responsive signaling cofactors and pathways in cortical and hippocampal neurons during hypoxia.Protein and Peptide Letters 05/2014; 21(5):444-51. DOI:10.2174/092986652105140218112521 · 1.74 Impact Factor