Bitransgenesis with β2-adrenergic receptors or adenylyl cyclase fails to Improve β1-adrenergic receptor cardiomyopathy

Abstract

Cardiomyopathic effects of β-adrenergic receptor (βAR) signaling are primarily due to the β1 AR subtype. β1/β2 AR and β1/ adenylyl cyclase type 5 (AC5) bitransgenic mice were created to test the hypothesis that β2 AR or AC5 co-overexpression has beneficial effects in β1 AR-mediated cardiomyopathy. In young mice, β1/β2 hearts had a greater increase in basal and isoproterenol-stimulated contractility compared to β1/AC5 and β1 AR hearts. By 6 months, β1 AR and β1/β2 hearts retained elevated basal contractility but were unresponsive to agonist. In contrast, β1/AC5 hearts maintained a small degree of agonist responsiveness, which may be due to a lack of β1 AR downregulation that was noted in β1- and β1/β2hearts. However, by 9-months, β1, β1/β2, and β1/AC5 mice had all developed severely depressed fractional shortening in vivo and little response to agonist. p38 mitogen activated protein kinase (MAPK) was minimally activated by β1AR, but was markedly enhanced in the bitransgenics. Akt activation was only found with the bitransgenics. The small increase in cystosolic second mitochondria-derived activator of caspase (Smac), indicative of apoptosis in 9-month β1AR hearts, was suppressed in β1/AC5, but not in β1/ β2, hearts. Taken together, the unique signaling effects of enhanced β2 AR and AC5, which have the potential to afford benefit in heart failure, failed to salvage ventricular function in β1 AR-mediated cardiomyopathy. © 2008 Wiley Periodicals, Inc.