Versatility of the Angiotensin II Type 1 Receptor

Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, 15th Floor, South Tower, 320 East North Ave, Pittsburgh, PA 15212. E-mail jsadoshi@pgh.auhs.edu

Key Words: angiotensin II type 1 receptor • cell growth • tyrosine kinase

This issue of Circulation Research includes 3 interesting studies that represent new concepts of AT₁ receptor–mediated cell signaling in the cardiovascular system, which is currently of intense interest. The AT₁ receptor mediates many important cardiovascular responses, including vasoconstriction, vascular and cardiac remodeling (cell proliferation, hypertrophy, and production of extracellular matrix), and cell survival/cell death. The AT₁ receptor belongs to the seven membrane–spanning GPCR family and typically activates PLCß through the heterotrimeric G_q protein, causing production of inositol trisphosphate and diacylglycerol. Besides this classical GPCR-G_q-PLCß pathway, recent studies indicate that Ang II activates both nonreceptor-type and receptor-type tyrosine kinases, which are typically activated by cytokine and EGFR stimulation. Activation of tyrosine kinases by Ang II is of great interest for a variety of reasons. First, tyrosine kinase–dependent signaling pathways mediate major growth effects of Ang II in cardiovascular systems.¹ Sayeski et al² reports that a 130-kDa protein, which is tyrosine-phosphorylated by Ang II, is identified as p130^Cas and that it potentially works as an effector of Src and PKC in VSMCs. Second, since the AT₁ receptor possesses neither intrinsic protein tyrosine kinase activities nor known physical association with tyrosine kinases except interaction with JAK2,³ the linkage between the AT₁ receptor and the tyrosine kinases was unexpected. Murasawa et al⁴ reports that Ang II transactivates the EGFR, which in turn mediates DNA synthesis in cardiac fibroblasts. Third, tyrosine kinases mediate activation of small GTP binding proteins (the Ras and Rho family) and downstream MAP kinases. Schmitz et al⁵ reports that Ang . . . [Full Text of this Article]

This article has been cited by other articles:

				P. Zhai, J. Galeotti, J. Liu, E. Holle, X. Yu, T. Wagner, and J. Sadoshima An Angiotensin II Type 1 Receptor Mutant Lacking Epidermal Growth Factor Receptor Transactivation Does Not Induce Angiotensin II-Mediated Cardiac Hypertrophy Circ. Res., September 1, 2006; 99(5): 528 - 536. [Abstract] [Full Text] [PDF]

				D. L. Hunton, W. G. Barnes, J. Kim, X.-R. Ren, J. D. Violin, E. Reiter, G. Milligan, D. D. Patel, and R. J. Lefkowitz {beta}-Arrestin 2-Dependent Angiotensin II Type 1A Receptor-Mediated Pathway of Chemotaxis Mol. Pharmacol., April 1, 2005; 67(4): 1229 - 1236. [Abstract] [Full Text] [PDF]

				W. G. Barnes, E. Reiter, J. D. Violin, X.-R. Ren, G. Milligan, and R. J. Lefkowitz {beta}-Arrestin 1 and G{alpha}q/11 Coordinately Activate RhoA and Stress Fiber Formation following Receptor Stimulation J. Biol. Chem., March 4, 2005; 280(9): 8041 - 8050. [Abstract] [Full Text] [PDF]

				J. B. C. Carvalheira, V. C. Calegari, H. G. Zecchin, W. Nadruz Jr., R. B. Guimaraes, E. B. Ribeiro, K. G. Franchini, L. A. Velloso, and M. J. A. Saad The Cross-Talk between Angiotensin and Insulin Differentially Affects Phosphatidylinositol 3-Kinase- and Mitogen-Activated Protein Kinase-Mediated Signaling in Rat Heart: Implications for Insulin Resistance Endocrinology, December 1, 2003; 144(12): 5604 - 5614. [Abstract] [Full Text] [PDF]

				K. Seta and J. Sadoshima Phosphorylation of Tyrosine 319 of the Angiotensin II Type 1 Receptor Mediates Angiotensin II-induced Trans-activation of the Epidermal Growth Factor Receptor J. Biol. Chem., March 7, 2003; 278(11): 9019 - 9026. [Abstract] [Full Text] [PDF]

				K. Seta, M. Nanamori, J. G. Modrall, R. R. Neubig, and J. Sadoshima AT1 Receptor Mutant Lacking Heterotrimeric G Protein Coupling Activates the Src-Ras-ERK Pathway without Nuclear Translocation of ERKs J. Biol. Chem., March 8, 2002; 277(11): 9268 - 9277. [Abstract] [Full Text] [PDF]

				C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]

				R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]

				A. D Hughes AT 1-signalling in vascular smooth muscle Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 125 - 130. [PDF]

				K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]

				R. M. Touyz, D. Endemann, G. He, J.-S. Li, and E. L. Schiffrin Role of AT2 Receptors in Angiotensin II–Stimulated Contraction of Small Mesenteric Arteries in Young SHR Hypertension, January 1, 1999; 33(1): 366 - 372. [Abstract] [Full Text] [PDF]

				G. G. N. Serneri, M. Boddi, I. Cecioni, S. Vanni, M. Coppo, M. L. Papa, B. Bandinelli, I. Bertolozzi, G. Polidori, T. Toscano, et al. Cardiac Angiotensin II Formation in the Clinical Course of Heart Failure and Its Relationship With Left Ventricular Function Circ. Res., May 11, 2001; 88(9): 961 - 968. [Abstract] [Full Text] [PDF]