title: Mild hypoxia induces hypertrophy of cultured neonatal rat cardiomyocytes: a possible endogenous endothelin-1-mediated mechanism.
abstract: Hypoxic or ischemic stresses on cardiomyocytes may cause a variety of compensatory responses including cell hypertrophy. In this study, we examined whether hypoxia induces hypertrophy of cardiomyocytes in vitro and whether hypoxia-induced hypertrophy is inhibited by an endothelin A receptor antagonist (BQ123). Neonatal rat cardiomyocytes were cultured in 10% O2/85% N2/5% CO2 or 95% N2/5% CO2 to produce a mild or severe hypoxic condition, respectively. Cardiomyocytes exposed to severe hypoxia revealed degenerative morphological changes and a decrease of cell number, suggesting the toxicity of severe hypoxia on cardiomyocytes. In contrast, cardiomyocytes with mild hypoxia developed hypertrophy; cell surface area of cardiomyocytes as evaluated by an image analyser system increased by 1.6-fold over control after 48 h. [3H]leucine incorporation into the cells was significantly increased by mild hypoxia but decreased by severe hypoxia, mRNA level of skeletal alpha-actin, a genetic marker of cardiac hypertrophy, up-regulated after 6-24 h by mild hypoxia. A transient increase of preproET-1 mRNA and a time-dependent increase of ET-1 protein in the culture medium were also observed in cardiomyocytes exposed to mild hypoxia. BQ123 partially inhibited either hypoxia-induced [3H]leucine incorporation or skeletal alpha-actin mRNA in a dose-dependent manner. These data suggest that mild hypoxia induces hypertrophy of cardiomyocytes and that activation of endogenous ET-1 may, at least in part, mediate this hypertrophic responses as an autocrine/ paracrine factor.
authors.affiliation: Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Adachi
authors.forename: M
authors.initials: M
authors.lastname: Tamamori
authors.forename: H
authors.initials: H
authors.lastname: Fujisaki
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: H
authors.initials: H
authors.lastname: Akimoto
authors.forename: F
authors.initials: F
authors.lastname: Marumo
authors.forename: M
authors.initials: M
authors.lastname: Hiroe
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000503:physiopathology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000502:physiology*; D016232:Endothelins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000502:physiology; D005819:Genetic Markers; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D007700:Kinetics; D007930:Leucine / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D011498:Protein Precursors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000199:Actins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D005819:Genetic Markers; D010456:Peptides, Cyclic; D011498:Protein Precursors; D012333:RNA, Messenger; D007930:Leucine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)