Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes

J Clin Invest. 1993 Jul;92(1):398-403. doi: 10.1172/JCI116579.


To elucidate the cellular mechanism by which angiotensin II (ANG II) induces cardiac hypertrophy, we investigated the possible autocrine/paracrine role of endogenous endothelin-1 (ET-1) in ANG II-induced hypertrophy of neonatal rat cardiomyocytes by use of synthetic ET-1 receptor antagonist and antisense oligonucleotides to preproET-1 (ppET-1) mRNA. Northern blot analysis and in situ hybridization revealed that ppET-1 mRNA was expressed in cardiomyocytes, but, to a lesser extent, in nonmyocytes as well. ANG II upregulated ppET-1 mRNA level by threefold over control level as early as 30 min, and it stimulated release of immunoreactive ET-1 from cardiomyocytes in a dose- and time-dependent manner. ET-1 stimulated ppET-1 mRNA levels after 30 min in a similar fashion as ANG II. Tetradecanoylphorbol-acetate (10(-7) M) mimicked the effects of ANG II and ET-1 on induction of ppET-1 mRNA. ANG II-induced ppET-1 gene expression was completely blocked by protein kinase C inhibitor H-7 or by down-regulation of endogenous protein kinase C by pretreatment with phorbol ester. ET-1 and ANG II stimulated twofold increase [3H]leucine incorporation into cardiomyocytes, whose effects were similarly and dose dependently inhibited by endothelin A receptor antagonist (BQ123). Introduction of antisense sequence against coding region of ppET-1 mRNA into cardiomyocytes resulted in complete blockade with ppET-1 mRNA levels and [3H]leucine incorporation stimulated by ANG II. These results suggest that endogenous ET-1 locally generated and secreted by cardiomyocytes may contribute to ANG II-induced cardiac hypertrophy via an autocrine/paracrine fashion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Base Sequence
  • Biphenyl Compounds / pharmacology
  • Cardiomegaly / etiology*
  • Cells, Cultured
  • Endothelin Receptor Antagonists
  • Endothelins / physiology*
  • Gene Expression / drug effects
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Losartan
  • Molecular Sequence Data
  • Muscle Proteins / biosynthesis
  • Myocardium / cytology*
  • Oligodeoxyribonucleotides / chemistry
  • Oligonucleotides, Antisense / pharmacology
  • Peptides, Cyclic / pharmacology
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Tetrazoles / pharmacology


  • Biphenyl Compounds
  • Endothelin Receptor Antagonists
  • Endothelins
  • Imidazoles
  • Muscle Proteins
  • Oligodeoxyribonucleotides
  • Oligonucleotides, Antisense
  • Peptides, Cyclic
  • RNA, Messenger
  • Tetrazoles
  • Angiotensin II
  • Losartan
  • cyclo(Trp-Asp-Pro-Val-Leu)