Nature Medicine
7, 1236 - 1240 (2001)
doi:10.1038/nm1101-1236
Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of G q/G11 in cardiomyocytesNina Wettschureck1, Hartmut Rütten2, Alexandra Zywietz1, Doris Gehring2, Tom M. Wilkie3, Ju Chen4, Kenneth R. Chien4
& Stefan Offermanns11
Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany
2
DG Cardiovascular, Aventis Pharma, Frankfurt, Germany
3
Pharmacology Department, University of Texas Southwestern Medical Center, Dallas, Texas, USA
4
Institute of Molecular Medicine, University of California, San Diego, La Jolla, California, USA
Correspondence should be addressed to Stefan Offermanns stefan.offermanns@urz.uni-heidelberg.deMyocardial 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  1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq -subunit, Gq, 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 Gq and G11 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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