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

Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality(1-3) due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors(2,3) and various downstream signaling pathways involving, for example, ras', gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase(7) 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 G(q/11)-, G(12/13)- and G(i/o)-families(5,6,8). Cardiomyocyte-specific transgenic overexpression of alpha (1)-adrenergic or angiotensin (AT(1))-receptors as well as of the G(q) alpha -subunit, G alpha (q), results in myocardial hypertrophy(9-12). These data demonstrate that chronic activation of the G(q)/G(11)-family is sufficient to induce myocardial hypertrophy. In order to test whether G(q)/G(11) mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both G alpha (q) and G alpha (11) 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 G(q)/G(11)-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.