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Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II

Abstract

The angiotensin II type 1 (AT1) receptor has a crucial role in load-induced cardiac hypertrophy. Here we show that the AT1 receptor can be activated by mechanical stress through an angiotensin-II-independent mechanism. Without the involvement of angiotensin II, mechanical stress not only activates extracellular-signal-regulated kinases and increases phosphoinositide production in vitro, but also induces cardiac hypertrophy in vivo. Mechanical stretch induces association of the AT1 receptor with Janus kinase 2, and translocation of G proteins into the cytosol. All of these events are inhibited by the AT1 receptor blocker candesartan. Thus, mechanical stress activates AT1 receptor independently of angiotensin II, and this activation can be inhibited by an inverse agonist of the AT1 receptor.

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GenBank/EMBL/DDBJ

Change history

  • 25 June 2004

    changed 'cardiomycytes' to 'cardiomyocytes'

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Acknowledgements

We thank R. J. Lefkowitz, J. Sadoshima and S. Kimura for plasmids; S.-i. Miura for advice; and A. Okubo, E. Fujita, R. Kobayashi and M. Watanabe for technical support. This work was supported by a Grant-in-Aid for Scientific Research, Developmental Scientific Research, and Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture; and by a grant for research on life science from Uehara Memorial Foundation, Japan (to I.K.).

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The authors declare no competing financial interests.

Correspondence to Issei Komuro.

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Figure 1: Activation of ERKs by mechanical stretch, AII and conditioned medium.
Figure 2: AII-independent activation of ERKs by mechanical stretch in cells overexpressing AT1 receptors.
Figure 3: Activation of G proteins and Jak2 by mechanical stretch, and their effects on ERK activation.
Figure 4: Mechanical-stretch-stimulated production of inositol phosphates through the AT1 receptor.
Figure 5: Cardiac hypertrophy in ATG−/− mice induced by pressure overload.