New Insights in Cardiac β-Adrenergic Signaling During Heart Failure and Aging

Abstract

Heart failure (HF) has become increasingly common within the elderly population, decreasing their survival and overall quality of life. In fact, despite the improvements in treatment, many elderly people suffer from cardiac dysfunction (HF, valvular diseases, arrhythmias or hypertension-induced cardiac hypertrophy) that are much more common in an older fragile heart. Since β-adrenergic receptor (β-AR) signaling is abnormal in failing as well as aged hearts, this pathway is an effective diagnostic and therapeutic target. Both HF and aging are characterized by activation/hyperactivity of various neurohormonal pathways, the most important of which is the sympathetic nervous system (SNS). SNS hyperactivity is initially a compensatory mechanism to stimulate contractility and maintain cardiac output. Unfortunately, this chronic stimulation becomes detrimental and causes decreased cardiac function as well as reduced inotropic reserve due to a decrease in cardiac β-ARs responsiveness. Therapies which (e.g., β-blockers and physical activity) restore β-ARs responsiveness can ameliorate cardiac performance and outcomes during HF, particularly in older patients. In this review, we will discuss physiological β-adrenergic signaling and its alterations in both HF and aging as well as the potential clinical application of targeting β-adrenergic signaling in these disease processes.

Keywords: GRK2; beta-adrenergic receptors; cardiac aging; cardiovascular system; heart failure; pharmacology; sympathetic nervous system.

FIGURE 1

Schematic representation of β-AR signaling in cardiomyocytes. See main text for details. CAs, catecholamines; β-AR, β-adrenergic receptor; G-protein subunits: G_α (G_αs or G_αi), G_β, G_γ; GRK2, G protein-coupled receptor kinase 2; AC, adenylyl cyclase; ATP, adenosine tri-phosphate; cAMP, cyclic adenosine mono-phosphate; PDE, phosphodiesterase; PKA, protein kinase A. A blue arrow is used when a stimulatory mechanism is involved while a red bar-headed line is used for an inhibitory mechanism.

FIGURE 2

β-AR signaling in cardiomyocytes under physiological condition (A), during heart failure (B), and during cardiac aging (C). Physiological conditions (A): GRK2 phosphorylates β-ARs in cardiomyocytes and regulates contractility via AC-PKA pathway activation. Heart failure (B): Increased circulating CAs led to hyper-stimulation of β-ARs and GRK2 upregulation in cardiomyocytes, resulting in desensitization/downregulation of β-ARs, ultimately leading to reduction of contractility. Aging heart (C): Aging is characterized by increased circulating CAs with desensitization/downregulation of cardiomyocyte β-ARs (GRK2 is unchanged and the mechanism of β-AR dysfunction is still unknown) and decreased contractility. AC activity is reduced leading to decreased levels of cAMP. CAs, catecholamines; β-AR, β-adrenergic receptor; G-protein subunits: G_α (G_αs or G_αi), G_β, G_γ; GRK2, G protein-coupled receptor kinase 2; AC, adenylyl cyclase; ATP, adenosine tri-phosphate; cAMP, cyclic adenosine mono-phosphate; PKA, protein kinase A. A blue arrow is used when a stimulatory mechanism is involved while a red bar-headed line is used for an inhibitory mechanism. Thicker arrow means upregulation while thinner arrow means downregulation.