Role of Beta-adrenergic Receptors and Sirtuin Signaling in the Heart During Aging, Heart Failure, and Adaptation to Stress.

Abstract

In the heart, catecholamine effects occur by activation of beta-adrenergic receptors (β-ARs), mainly the beta 1 (β1-AR) and beta 2 (β2-AR) subtypes, both of which couple to the Gs protein that activates the adenylyl cyclase signaling pathway. The β2-ARs can also couple to the Gi protein that counterbalances the effect of the Gs protein on cyclic adenosine monophosphate production and activates the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In several cardiovascular disorders, including heart failure, as well as in aging and in animal models of environmental stress, a reduction in the β1/β2-AR ratio and activation of the β2-AR-Gi-PI3K-Akt signaling pathway have been observed. Recent studies have shown that sirtuins modulate certain organic processes, including the cellular stress response, through activation of the PI3K-Akt signaling pathway and of downstream molecules such as p53, Akt, HIF1-α, and nuclear factor-kappa B. In the heart, SIRT1, SIRT3, and β2-ARs are crucial to the regulation of the cardiomyocyte energy metabolism, oxidative stress, reactive oxygen species production, and autophagy. SIRT1 and the β2-AR-Gi complex also control signaling pathways of cell survival and death. Here, we review the role played by β2-ARs and sirtuins during aging, heart failure, and adaptation to stress, focusing on the putative interplay between the two. That relationship, if proven, merits further investigation in the context of cardiac function and dysfunction.