A Novel Mechanism of Mechanical Stress-Induced Hypertrophy

  1. Gregory Bock Organizer and
  2. Jamie Goode
  1. Hiroshi Akazawa,
  2. Yunzeng Zou and
  3. Issei Komuro

Published Online: 7 OCT 2008

DOI: 10.1002/0470029331.ch3

Heart Failure: Molecules, Mechanisms and Therapeutic Targets: Novartis Foundation Symposium 274

Heart Failure: Molecules, Mechanisms and Therapeutic Targets: Novartis Foundation Symposium 274

How to Cite

Akazawa, H., Zou, Y. and Komuro, I. (2006) A Novel Mechanism of Mechanical Stress-Induced Hypertrophy, in Heart Failure: Molecules, Mechanisms and Therapeutic Targets: Novartis Foundation Symposium 274 (eds G. Bock and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470029331.ch3

Author Information

  1. Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan

  1. This paper was presented at the symposium by Issei Komuro, to whom all correspondence should be addressed.

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 27 JUL 2006

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470015971

Online ISBN: 9780470029336

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Keywords:

  • Angiotensin II (AII) type 1 (AT1) receptor in load-induced cardiac hypertrophy;
  • cardiac hypertrophy and increased workload;
  • AII-independent activation of AT1 receptor by stretch;
  • mechanical stress and haemodynamic overload;
  • extracellular signal-regulated protein kinases (ERKs);
  • cell culture and transfection;
  • inositol phosphate detection;
  • TAC operation and haemodynamic measurements

Summary

Angiotensin II (AII) type 1 (AT1) receptor plays a critical role in load-induced cardiac hypertrophy. We have recently found a novel mechanism of mechanical stress-induced activation of the AT1 receptor, which is independent of AII. Mechanical stretch did not activate ERKs in HEK293 cells and COS7 cells which had no AT1 receptor, but when AT1 receptor was overexpressed in these cells, stretch activated ERKs, Gαq and JAK2. An AT1 receptor blocker, candesartan, inhibited stretch-induced activation of ERKs in these cells. Stretch also activated ERKs in COS7 cells expressing AT1 mutant which did not bind AII and in cardiac myocytes prepared from angiotensinogen null mice. Stretch did not activate ERKs in COS7 cells which overexpressed ETA receptor and β-adrenergic receptor. Pressure overload induced cardiac hypertrophy in angiotensinogen null mice as well as in wild-type mice, which was significantly inhibited by candesartan. These results suggest that mechanical stress activates AT1 receptor independently of AII, which is inhibited by an inverse agonist candesartan.