title: Regulation of myoglobin in hypertrophied rat cardiomyocytes in experimental pulmonary hypertension.
abstract: A major problem in chronic heart failure is the inability of hypertrophied cardiomyocytes to maintain the required power output. A Hill-type oxygen diffusion model predicts that oxygen supply is limiting in hypertrophied cardiomyocytes at maximal rates of oxygen consumption and that this limitation can be reduced by increasing the myoglobin (Mb) concentration. We explored how cardiac hypertrophy, oxidative capacity, and Mb expression in right ventricular cardiomyocytes are regulated at the transcriptional and translational levels in an early stage of experimental pulmonary hypertension, in order to identify targets to improve the oxygen supply/demand ratio. Male Wistar rats were injected with monocrotaline to induce pulmonary hypertension (PH) and right ventricular heart failure. The messenger RNA (mRNA) expression levels per nucleus of growth factors insulin-like growth factor-1Ea (IGF-1Ea) and mechano growth factor (MGF) were higher in PH than in healthy controls, consistent with a doubling in cardiomyocyte cross-sectional area (CSA). Succinate dehydrogenase (SDH) activity was unaltered, indicating that oxidative capacity per cell increased. Although the Mb protein concentration was unchanged, Mb mRNA concentration was reduced. However, total RNA per nucleus was about threefold higher in PH rats versus controls, and Mb mRNA content expressed per nucleus was similar in the two groups. The increase in oxidative capacity without an increase in oxygen supply via Mb-facilitated diffusion caused a doubling of the critical extracellular oxygen tension required to prevent hypoxia (PO2crit). We conclude that Mb mRNA expression is not increased during pressure overload-induced right ventricular hypertrophy and that the increase in myoglobin content per myocyte is likely due to increased translation. We conclude that increasing Mb mRNA expression may be beneficial in the treatment of experimental PH.
authors: Laboratory for Myology, Faculty of Behavioral and Movement Sciences, Department of Human Movement Sciences, MOVE Research Institute Amsterdam, Vrije Universiteit Amsterdam, van der Boechorststraat 7, 1081, BT, Amsterdam, The Netherlands.
authors: E L
authors: EL
authors: Peters
authors: Laboratory for Myology, Faculty of Behavioral and Movement Sciences, Department of Human Movement Sciences, MOVE Research Institute Amsterdam, Vrije Universiteit Amsterdam, van der Boechorststraat 7, 1081, BT, Amsterdam, The Netherlands.
authors: C
authors: C
authors: Offringa
authors: Laboratory for Myology, Faculty of Behavioral and Movement Sciences, Department of Human Movement Sciences, MOVE Research Institute Amsterdam, Vrije Universiteit Amsterdam, van der Boechorststraat 7, 1081, BT, Amsterdam, The Netherlands.|Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors: D
authors: D
authors: Kos
authors: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors: W J
authors: WJ
authors: Van der Laarse
authors: Laboratory for Myology, Faculty of Behavioral and Movement Sciences, Department of Human Movement Sciences, MOVE Research Institute Amsterdam, Vrije Universiteit Amsterdam, van der Boechorststraat 7, 1081, BT, Amsterdam, The Netherlands. r.t.jaspers@vu.nl.
authors: R T
authors: RT
authors: Jaspers
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism*; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009211:Myoglobin / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D009211:Myoglobin; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013385:Succinate Dehydrogenase; D010100:Oxygen
keywords: Cardiac myocyte; Growth factor; Heart failure; Hypertrophy; Mitochondrial biosynthesis; Myoglobin; Oxidative capacity; Protein degradation; Protein synthesis; Pulmonary hypertension