Mild hypoxia induces hypertrophy of cultured neonatal rat cardiomyocytes: a possible endogenous endothelin-1-mediated mechanism

J Mol Cell Cardiol. 1996 Jun;28(6):1271-7. doi: 10.1006/jmcc.1996.0117.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / biosynthesis
  • Animals
  • Animals, Newborn
  • Cardiomegaly / physiopathology*
  • Cell Hypoxia
  • Cells, Cultured
  • Endothelin Receptor Antagonists
  • Endothelin-1 / biosynthesis
  • Endothelin-1 / physiology*
  • Endothelins / biosynthesis
  • Gene Expression Regulation / physiology
  • Genetic Markers
  • Heart / physiology*
  • Heart / physiopathology
  • Kinetics
  • Leucine / metabolism
  • Myocardium / cytology*
  • Myocardium / metabolism
  • Peptides, Cyclic / pharmacology
  • Protein Precursors / biosynthesis
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Time Factors
  • Transcription, Genetic* / drug effects

Substances

  • Actins
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Endothelins
  • Genetic Markers
  • Peptides, Cyclic
  • Protein Precursors
  • RNA, Messenger
  • Leucine
  • cyclo(Trp-Asp-Pro-Val-Leu)