Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts

Cardiovasc Res. 1998 Nov;40(2):352-63. doi: 10.1016/s0008-6363(98)00121-7.


Objective: We sought to determine whether angiotensin II (Ang II) promotes hypertrophy of cardiac directly or via paracrine mechanisms mediated by cardiac fibroblasts.

Methods: We studied neonatal rat cardiac myocytes and fibroblasts in culture as a model system. Paracrine effects of Ang II were identified using conditioned medium and co-culture experiments.

Results: Ang II type 1 (AT1) receptors responsible for myocyte growth localized to fibroblasts in radioligand binding, emulsion autoradiography, Western analysis, and immunofluorescence staining experiments. The bulk of AT1 receptor binding in myocyte cultures (1343 +/- 472 sites/cell) was to Ang II receptors on contaminating fibroblasts (9747 +/- 2126 sites/cell). Ang II induced significant paracrine trophic effects on myocytes in conditioned medium (40% increase in protein synthesis over control) and co-culture (4-fold increase over control) experiments. TGF-beta 1 and endothelin-1 were paracrine mediators of hypertrophy in neutralization experiments.

Conclusions: Ang II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from cardiac fibroblasts in a neonatal rat cell culture model.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Animals, Newborn
  • Blotting, Northern
  • Blotting, Western
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cells, Cultured
  • Coculture Techniques
  • Culture Media, Conditioned / pharmacology
  • Endothelin-1 / analysis
  • Endothelin-1 / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Microscopy, Fluorescence
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Paracrine Communication*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Angiotensin / genetics
  • Receptors, Angiotensin / metabolism
  • Transforming Growth Factor beta / analysis
  • Transforming Growth Factor beta / metabolism*
  • Vasoconstrictor Agents / pharmacology*


  • Culture Media, Conditioned
  • Endothelin-1
  • RNA, Messenger
  • Receptors, Angiotensin
  • Transforming Growth Factor beta
  • Vasoconstrictor Agents
  • Angiotensin II