title: A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology.
abstract: Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed.
authors.affiliation: Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia. Electronic address: pbala2006@gmail.com.
authors.forename: Pitchai
authors.initials: P
authors.lastname: Balakumar
authors.affiliation: Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: Gowra.Jagadeesh@fda.hhs.gov.
authors.forename: Gowraganahalli
authors.initials: G
authors.lastname: Jagadeesh
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D019390:Arrestins / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000503:physiopathology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006801:Humans; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D050791:STAT Transcription Factors; D000071557:beta-Arrestins; D000804:Angiotensin II; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: AT(1) receptor signal transduction; Alamandine; G protein-dependent and-independent signals; RAS components; Transactivation cascades