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.

Keywords: Adrenergic receptors; Aging; Environmental stress; Heart failure; Sirtuins.

Fig. 1

Schematic representation of the beta 1- and beta 2-adrenergic receptor (β₁-AR and β₂-AR, respectively) signaling pathways in cardiomyocytes via the coupling of the receptors to the Gs protein. Gs stimulatory G protein, AC adenylyl cyclase, ATP adenosine triphosphate, cAMP cyclic adenosine monophosphate, PKA protein kinase, Epac exchange protein directly activated by cAMP, ERK extracellular signal-regulated kinase, + stimulatory effect

Fig. 2

Schematic representation of the beta 2-adrenergic receptor (β₂-AR)-Gi protein signaling pathway. Gi inhibitory G protein, α _i Gi alpha subunit, βγ Gi protein beta–gamma subunit, AC adenylyl cyclase, PI3K phosphatidylinositol 3-kinase, mTOR mammalian target of rapamycin, P70S6K ribosomal protein S6 kinase beta-1, FoxO forkhead box O transcription factor, MAFbx muscle atrophy F-box, MuRF1 muscle RING finger 1 protein

Fig. 3

Schematic representation of sirtuin 1 (SIRT1) signaling in the heart. mTOR mammalian target of rapamycin, FoxO1 forkhead box O1 transcription factor, MuRF1 muscle RING finger 1 protein, NF-κB nuclear factor-kappa B, HIF1-α hypoxia-inducible factor 1-alpha, PGC-1α peroxisome proliferator-activated receptor-gamma coactivator. The arrows indicate stimulation, and the lines with whiskers indicate inhibition

Fig. 4

Schematic representation of sirtuin 3 (SIRT3) signaling in the heart. FoxO3 forkhead box O3 transcription factor, MuRF1 muscle RING finger 1 protein, NF-κB nuclear factor-kappa B, ROS reactive oxygen species, MAPK mitogen-activated protein kinase, ERK1/2 extracellular signal-regulated kinases 1/2, PKC protein kinase C, JNK c-Jun N-terminal kinase, PI3K phosphatidylinositol 3-kinase. The arrows indicate stimulation, and the lines with whiskers indicate inhibition

Fig. 5

Schematic representation of a putative interplay between β₂-adrenergic receptor (β₂-AR)-Gi-PI3K signaling and sirtuin (SIRT1 and SIRT3) signaling pathway in the heart. Gi inhibitory G protein, PI3K phosphatidylinositol 3-kinase, mTOR mammalian target of rapamycin, FoxO forkhead box O transcription factor, MnSOD mitochondrial antioxidant manganese superoxide dismutase, Rab7 Ras-related protein, PGC-1α peroxisome proliferator-activated receptor-gamma coactivator. The arrows indicate stimulation, the lines with whiskers indicate inhibition, and the dashed line indicates an unknown putative relationship between β₂-ARs and sirtuins