Potentiation of beta-adrenergic signaling by gene transfer.
The beta-adrenergic signaling cascade is an important regulator of myocardial function. Numerous abnormalities occur in this pathway and are associated with impaired cardiac contractility in patients with congestive heart failure (CHF). These signaling defects include downregulation of beta-adrenergic receptors (beta ARs) and increased levels of beta-adrenergic receptor kinase (beta ARK), an enzyme that phosphorylates and uncouples only agonist-bound receptors. Our laboratory has been testing the hypothesis that reversal of these beta-adrenergic defects may be able to restore cardiac inotropy to normal in patients with depressed systolic function. Transgenic mice with cardiac overexpression of beta 2ARs or an inhibitor of beta ARK have enhanced cardiac function as compared to wildtype littermates. Adenoviral vectors encoding the beta 2AR or beta ARK inhibitor potentiate beta AR signaling in cultured adult rabbit ventricular myocytes. However, a controversy has developed in the literature regarding whether increasing beta-adrenergic signaling would be beneficial or detrimental for patients with CHF. Those cautioning against this approach note that increased sympathetic activity is dangerous in CHF. Elevated catecholamine levels predict mortality and beta-agonists are not beneficial for survival, while recent studies suggest that beta-antagonists do improve outcome. Supporting these concerns is the demonstration that transgenic mice with cardiac overexpression of Gs alpha and enhanced myocardial responsiveness to isoproterenol develop myocardial fibrosis. This article summarizes this controversy; highlights important differences between overexpression of beta ARs or a beta ARK inhibitor, overexpression of Gs alpha, and administration of beta-agonists; and develops the hypothesis that these strategies may differ in their therapeutic efficacy in treating CHF.
Drazner, MH; Koch, WJ; Lefkowitz, RJ
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