Insights Into the Role of Angiotensin-II AT1 Receptor-Dependent β-Arrestin Signaling in Cardiovascular Disease

Abstract

β-arrestins are a family of intracellular signaling proteins that play a key role in regulating the activity of G protein-coupled receptors. The angiotensin-II type 1 receptor is an important G protein-coupled receptor involved in the regulation of cardiovascular function and has been implicated in the progression of cardiovascular diseases. In addition to canonical G protein signaling, G protein-coupled receptors including the angiotensin-II type 1 receptor can signal via β-arrestin. Dysregulation of β-arrestin signaling has been linked to several cardiovascular diseases including hypertension, atherosclerosis, and heart failure. Understanding the role of β-arrestins in these conditions is critical to provide new therapeutic targets for the treatment of cardiovascular disease. In this review, we will discuss the beneficial and maladaptive physiological outcomes of angiotensin-II type 1 receptor-dependent β-arrestin activation in different cardiovascular diseases.

Keywords: G protein coupled receptors; angiotensin receptor; hypertension; pharmacology; renin-angiotensin system.

Figure 1.. G-protein and β-arrestin activation upon a balanced ligand, AngII.

When Ang II binds to its receptor, the Gα subunit of the G-protein complex dissociates from Gβγ, activating second messenger pathways such as cAMP, PLC, and Rho/Rac. This response leads to increased vascular resistance, cardiac contractility, fluid intake, and sympathetic outflow. However, the signaling can be suppressed through the phosphorylation of the receptor by G-protein receptor kinases, which leads to the binding of the adaptor protein β-arrestin. Activation of β-arrestin promotes internalization of the receptor, resulting in signal desensitization and β-arrestin-dependent signaling.

Figure 2.. Role of β-arrestin2 in saline intake and blood pressure.

The use of biased ligand TRV027 to activate AT₁R-β-arrestin pathway has shown to reduce blood pressure and decrease salt consumption during DOCA-salt hypertension. Further, mice carrying deletion of β-arrestin2 showed increase in salt consumption and further increase in blood pressure. These contrasting findings suggest the role of β-arrestin2 but not β-arrestin1 in mediating the cardiovascular benefit seen with the use of TRV027.

Figure 3.. Chronic Physiologic Consequences of β-arrestin activation downstream of the AT₁R.

Schematic illustration of AT₁R-dependent physiologic consequences of β-arrestin activation in various organ systems. Activation of β-arrestin have been found to be beneficial (shown in green) or maladaptive (shown in red) depending on the organ system, disease stage, the mechanism of β-arrestin activation and the interaction with downstream effectors.