TRANSGENIC G-ALPHA-Q OVEREXPRESSION INDUCES CARDIAC CONTRACTILE FAILURE IN MICE

The critical cell signals that trigger cardiac hypertrophy and regulat e the transition to heart failure are not known. To determine the role of G alpha q-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type G alpha q in the he art using the alpha-myosin heavy chain promoter. Two-fold overexpressi on of G alpha q showed no detectable effects, whereas 4-fold overexpre ssion resulted in increased heart weight and myocyte size along with m arked increases in atrial naturietic factor (approximate to 55-fold), beta-myosin heavy chain (approximate to 8-fold), and alpha-skeletal ac tin (approximate to 8-fold) expression, and decreased (approximate to 3-fold) beta-adrenergic receptor-stimulated adenylyl cyclase activity, All of these signals have been considered markers of hypertrophy or f ailure in other experimental systems or human heart failure, Echocardi ography and in vivo cardiac hemodynamic studies indeed revealed impair ed intrinsic contractility manifested as decreased fractional shorteni ng (19 +/- 2% vs, 41 +/- 3%), dP/dt max, a negative force-frequency re sponse, an altered Starling relationship, and blunted contractile resp onses to the beta-adrenergic agonist dobutamine, At higher levels of G alpha q overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary conges tion, and death, The element within the pathway that appeared to be cr itical for these events was activation of protein kinase C epsilon. In terestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated, Th e G alpha q overexpressor exhibits a biochemical and physiologic pheno type resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathoge nesis.