Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice

Transgenic overexpression of G alpha q in the heart triggers events leading to a phenotype of eccentric hypertrophy, depressed ventricular function, marked expression of hypertrophy-associated genes, and depressed beta-adrenergic receptor (beta AR) function. The role of beta AR dysfunction in the development of this failure phenotype was delineated by transgenic coexpression of the carboxyl terminus of the beta AR kinase (beta ARK), which acts to inhibit the kinase, or concomitant overexpression of the beta(2)AR at low (approximate to 30-fold, G alpha q/beta(2)AR(L)), moderate (approximate to 140-fold, G alpha q/beta(2)AR(M)), and high (approximate to 1,000-fold, G alpha q/beta(2)AR(H)) levels above background beta AR density. Expression of the beta ARK inhibitor had no effect on the phenotype, consistent with the lack of increased beta ARK levels in G alpha q mice. In marked contrast, G alpha q/beta(2)AR(L) mice displayed rescue of hypertrophy and resting ventricular function and decreased cardiac expression of atrial natriuretic factor and alpha-skeletal actin mRNA. These effects occurred in the absence of any improvement in basal or agonist-stimulated adenylyl cyclase (AC) activities in crude cardiac membranes, although restoration of a compartmentalized beta(2)AR/AC signal cannot be excluded. Higher expression of receptors in G alpha q/beta(2)AR(M) mice resulted in salvage of AC activity, but hypertrophy, ventricular function, and expression of fetal genes were unaffected or worsened. With approximate to 1,000-fold overexpression, the majority of G alpha q/beta(2)AR(H) mice died with cardiomegaly at 5 weeks. Thus, although it appears that excessive, uncontrolled, or generalized augmentation of X AR signaling is deleterious in heart failure, selective enhancement by overexpressing the beta(2)AR subtype to limited levels restores not only ventricular function but also reverses cardiac hypertrophy.