AT1 receptor signaling pathways in the cardiovascular system

Abstract

The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system.

Keywords: ADAM17; Angiotensin II; EGF receptor; Endothelial cell; Signal transduction; Vascular smooth muscle cell.

Figure 1. AT1 receptor signal transduction cascade through EGFR transactivation

AngII-activated AT1 receptor initiates classical second messenger-mediated signals such as Ca2+, elevation and PKC activation as well as PTK activation and ROS production via heterotrimeric G proteins, which then activate ADAM17 via phosphorylation. Activated ADAM17 causes shedding of EGFR ligands such as pro-HB-EGF, and activates EGFR. EGFR transactivation by AT1 receptor facilitates cellular hypertrophy, proliferation and migration via the Ras/Raf/MEK/ERK pathway and PI3K/Akt-PKB/mTOR pathway. EGFR: epidermal growth factor receptor; ADAM17: A Disintegrin And Metalloproteinase 17; MEK: MAPK/ERK kinase; mTOR: mamalian target of rapamycin; eIF4E: eukaryotic translation initiation factor 4E.

Figure 2. AT1 receptor signal transduction cascade through the Rho/ROCK pathway

The AT1 receptor interacts with heterotrimeric G proteins and activates Rho/ROCK pathway via RhoGEF. Through this pathway, AT1 receptor stimulates cellular contraction via MLC by inhibition of MLCP, cellular proliferation/hypertrophy via JNK, and inflammation via PAI-1/MCP-1. MLC: myosin light chain; MLCP: MLC phosphatase.

Figure 3. The new and complex mechanisms of AT1 receptor-mediated signaling in cardiovascular pathophysiology

Traditionally AT1 receptor is known to cause cardiovascular remodeling, hypertension and end organ damage via a few cascades including Gq/Ca²⁺-PKC, ERK/MAPK and NOX/ROS. Although not all the functional significances have been identified, recent studies explored new signaling mechanisms by which the AT1 receptor may contribute to cardiovascular disorders, including Wnt, Notch, mitochondrial regulation and AT1 receptor interacting proteins. Elucidating the complexity of AT1 receptor signaling seems to be on the forefront of RAAS research to conquer cardiovascular disorders.