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Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Gαq/Gα11 in cardiomyocytes

Nature Medicine volume 7, pages 1236–1240 (2001)Cite this article

Abstract

Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality1,2,3 due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors2,3 and various downstream signaling pathways involving, for example, ras4, gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase7 have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families5,6,8. Cardiomyocyte-specific transgenic overexpression of α1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq α-subunit, Gαq, results in myocardial hypertrophy9,10,11,12. These data demonstrate that chronic activation of the Gq/G11-family is sufficient to induce myocardial hypertrophy. In order to test whether Gq/G11 mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Gαq and Gα11 in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the Gq/G11-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.

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Figure 1: Generation of gnaqflox mice and cardiomyocyte-specific deletion of the gnaqflox allele.
Figure 2: Effect of pressure overload on Gαq/Gα11-deficient hearts.

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Acknowledgements

We thank Y. Fujiwara and S. Orkin for Cre reporter mouse strain; H. Westphal for EIIa-Cre mice; E. Rohde for help with blastocyst injection; and K. Wartemann and A. Rogatzki for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany

    Nina Wettschureck, Alexandra Zywietz & Stefan Offermanns

  2. DG Cardiovascular, Aventis Pharma, Frankfurt, Germany

    Hartmut Rütten & Doris Gehring

  3. Pharmacology Department, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Tom M. Wilkie

  4. Institute of Molecular Medicine, University of California, San Diego, La Jolla, California, USA

    Ju Chen & Kenneth R. Chien

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  1. Nina Wettschureck
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Correspondence to Stefan Offermanns.

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Wettschureck, N., Rütten, H., Zywietz, A. et al. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Gαq/Gα11 in cardiomyocytes. Nat Med 7, 1236–1240 (2001). https://doi.org/10.1038/nm1101-1236

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