Changes in myosin heavy chain and its localization in rat heart in association with hypobaric hypoxia-induced pulmonary hypertension.
ABSTRACT Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodelling of the heart. In rat cardiac ventricles, pressure and volume overload are well known to be associated with changes in cardiac myosin heavy chain (MHC) isoforms. To study the effects of HHE on the MHC profile in the ventricles, 83 male Wistar rats were housed in a chamber at the equivalent of 5500 m altitude for 1-8 weeks. Pulmonary arterial pressure, right ventricular free wall (RVFW) weight, the ratio of RVFW weight over body weight (BW), the ratio of left ventricular free wall (LVFW) weight over BW, and myocyte diameter in both ventricles showed significant increases after 1 week, 2 weeks, 1 week, 6 weeks, and 4 weeks of HHE, respectively. Semi-quantitative reverse transcriptase-polymerase chain reaction revealed that beta-MHC mRNA expression was increased significantly in both ventricles at 6 and 8 weeks of HHE, whereas alpha-MHC mRNA expression was decreased significantly at 6 and 8 weeks of HHE in the right ventricle (RV) and at 6 weeks of HHE in the left ventricle (LV). The percentage of myosin containing the beta-MHC isoform was increased significantly at 4-8 weeks of HHE in RV and at 6 weeks of HHE in LV. In situ hybridization showed that the area of strong staining for beta-MHC mRNA was increased in both ventricles at 8 weeks of HHE, and showed a decrease from RVFW to cardiac septum, and from cardiac septum to LVFW. These results suggest that HHE has a significant effect on the expression of both MHC mRNA and protein in the heart, particularly in RV. These changes may reflect a role for cardiac MHC in the response to pulmonary hypertension in HHE.
- SourceAvailable from: Christophe M R LeMoine[Show abstract] [Hide abstract]
ABSTRACT: In mammals, environmental challenges often result in physical and metabolic cardiac remodeling (i.e., hypertrophy and a shift from lipid to carbohydrate oxidation). While chronic hypoxia and cold are both known to elicit cardiac changes, little is known about their combined effects. To investigate the cumulated effects of these two stressors on cardiac physiology, CD-1 mice were exposed for 4 weeks to normoxia/normothermia, hypoxia, cold, or combined hypoxic-cold. We assessed physical characteristics, left ventricular activities of fatty acid catabolic enzymes short-chain β-hydroxyacyl-CoA dehydrogenase (SCHAD) and medium-chain acyl-CoA dehydrogenase, and mRNA levels of Acadm, muscle- and liver-type carnitine palmitoyltransferase (Cpt-1β, Cpt-1α), and the transcriptional regulator PPARα. 1) Chronic hypoxia reduced SCHAD activity without physical remodeling or mRNA changes; 2) chronic cold lead to reduced SCHAD activity in hypertrophied left ventricles and lowered right ventricular Cpt-1α mRNA (compared to chronic hypoxia); and 3) despite causing hypertrophy of both ventricles, chronic exposure to combined hypoxic-cold did not induce significant metabolic remodeling. In response to environmental challenges, cardiac muscles 1) show distinct physical and metabolic remodeling, 2) respond to two stressors simultaneously but not additively, and 3) maintain an adult metabolic phenotype with long-term exposure to environmentally realistic hypoxic-cold.Biochimica et Biophysica Acta 12/2010; 1800(12):1248-55. · 4.66 Impact Factor
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ABSTRACT: Aim: Protein kinase C (PKC), cloned as a serine/threonine kinase, plays key roles in diverse intracellular signalling processes and in cardiovascular remodelling during pressure overload or volume overload. We looked for correlations between changes in PKC isoforms (levels and/or subcellular distributions) and cardiac remodelling during experimental hypobaric hypoxic environment (HHE)-induced pulmonary hypertension.Methods: To study the PKC system in the heart during HHE, 148 male Wistar rats were housed for up to 21 days in a chamber at the equivalent of 5500 m altitude level (10% O2).Results: At 14 or more days of exposure to HHE, pulmonary arterial pressure (PAP) was significantly increased. In the right ventricle (RV): (1) the expression of PKC-α protein in the cytosolic and membrane fractions was increased at 3–14 days and at 5–7 days of exposure respectively; (ii) the cytosolic expression of PKC-δ protein was increased at 1–5, 14 and 21 days of exposure; (3) the membrane expressions of the proteins were decreased at 14–21 (PKC-βII), 14–21 (PKC-γ), and 0.5–5 and 21 (PKC-ε) days of exposure; (4) the expression of the active form of PKC-α protein on the plasma membrane was increased at 3 days of exposure (based on semiquantitative analysis of the immunohistochemistry). In the left ventricle, the expressions of the PKC mRNAs, and of their cytosolic and membrane proteins, were almost unchanged. The above changes in PKC-α, which were strongly evident in the RV, occurred alongside the increase in PAP.Conclusion: PKC-α may help to modulate the right ventricular hypertrophy caused by pulmonary hypertension in HHE.Acta Physiologica 11/2009; 198(4):431 - 440. · 4.38 Impact Factor
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ABSTRACT: Right ventricular hypertrophy and right heart failure occur in patients with pulmonary hypertension. The mechanisms of left ventricular hypertrophy are well understood, however, information on right ventricular hypertrophy is limited. Studies of embryonic and adult hearts provided evidence that the molecular signaling mechanisms are different for right and left ventricles. Thus, the development of therapeutic strategies specific for the right heart is needed. This chapter summarizes current understanding of cell growth signaling mechanisms in the right ventricle.