Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of G alpha(q)/G alpha(11) in cardiomyocytes

Myocardial hypertrophy is an adaptational response of the heart to increase d work load, but it is also associated with a high risk of cardiac mortalit y(1-3) due to its established role in the development of cardiac failure, o ne of the leading causes of death in developed countries. Multiple growth f actors(2,3) and various downstream signaling pathways involving, for exampl e, ras', gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kina se(7) have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertroph y involves the formation of cardiac para- and/or autocrine factors like end othelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of w hich are coupled to G-proteins of the G(q/11)-, G(12/13)- and G(i/o)-famili es(5,6,8). Cardiomyocyte-specific transgenic overexpression of alpha (1)-ad renergic or angiotensin (AT(1))-receptors as well as of the G(q) alpha -sub unit, G alpha (q), results in myocardial hypertrophy(9-12). These data demo nstrate that chronic activation of the G(q)/G(11)-family is sufficient to i nduce myocardial hypertrophy. In order to test whether G(q)/G(11) mediate t he physiological hypertrophy response to pressure overload, we generated a mouse line lacking both G alpha (q) and G alpha (11) in cardiomyocytes. The se mice showed no detectable ventricular hypertrophy in response to pressur e-overload induced by aortic constriction. The complete lack of a hypertrop hic response proves that the G(q)/G(11)-mediated pathway is essential for c ardiac hypertrophy induced by pressure overload and makes this signaling pr ocess an interesting target for interventions to prevent myocardial hypertr ophy.