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 (β-AR) and beta 2 (β-AR) subtypes, both of which couple to the Gs protein that activates the adenylyl cyclase signaling pathway. The β-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 β/β-AR ratio and activation of the β-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 β-ARs are crucial to the regulation of the cardiomyocyte energy metabolism, oxidative stress, reactive oxygen species production, and autophagy. SIRT1 and the β-AR-Gi complex also control signaling pathways of cell survival and death. Here, we review the role played by β-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.

Derangements in adrenergic–adipokine signalling establish a neurohormonal basis for obesity‐related heart failure with a preserved ejection fraction

“…Additionally, although beta 2 ‐receptor stimulation causes lipolysis and suppresses the secretion of leptin in healthy adipose tissue, these adrenergic responses are attenuated in epicardial fat . Instead, beta 2 ‐adrenergic stimulation of epicardial adipose tissue promotes activation of the p53 senescence pathway, and both beta 2 ‐receptors and p53 have been implicated in the pathogenesis of adipose tissue and cardiac inflammation and of aging‐related heart disease, especially HFpEF . Intriguingly, beta 2 ‐adrenergic receptors may also be involved in systemic inflammation; their stimulation can enhance the synthesis of pro‐inflammatory cytokines .…”

Sirtuins as Mediator of the Anti-Ageing Effects of Calorie Restriction in Skeletal and Cardiac Muscle

“…Indeed, SIRT1 has been demonstrated to be protective against endothelial dysfunction, atherothrombosis, and myocardial infarction [ 146 ]. Interestingly, the interplay between sirtuins and beta-adrenergic receptors has been hypothesized, thus opening a new scenario for the molecular changes occurring in the heart during ageing and diseases [ 147 ].…”

Impact of stress on aged immune system compartments: Overview from fundamental to clinical data

“…Follow-up studies including pharmacological intervention showed that mTORC1 pathway and probably the sirtuins are involved in the lifespan-boosting effects of caloric restriction (reviewed in [71]). Animal models of environmental stress show a reduction in the B1/B2-AR ratio and activation of the Beta2-AR-Gi-PI3K-Akt signalling pathway and of downstream molecules such as p53, Akt, HIF1alpha and NF-κB, a cellular stress responses associated with heart failure [72].…”