Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression

J Clin Invest. 1995 Aug;96(2):1059-65. doi: 10.1172/JCI118092.


The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / antagonists & inhibitors*
  • Angiotensin II / pharmacology
  • Animals
  • Atrial Natriuretic Factor / pharmacology*
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / pharmacology
  • DNA, Complementary / genetics
  • Endothelins / biosynthesis
  • Endothelins / genetics
  • Endothelins / physiology*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Myocardium / cytology*
  • Natriuretic Peptide, Brain
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / pharmacology*
  • Nitroprusside / pharmacology
  • Rats


  • DNA, Complementary
  • Endothelins
  • Nerve Tissue Proteins
  • brain natriuretic peptide-35, rat
  • Angiotensin II
  • Natriuretic Peptide, Brain
  • Nitroprusside
  • 8-bromocyclic GMP
  • Atrial Natriuretic Factor
  • Cyclic GMP