© 1998 American Heart Association, Inc.
Review |
Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases
From the Department of Medicine II, Division of Endocrine Hypertension and Metabolism and Nephrology, Kansai Medical University, Moriguchi, Osaka, Japan.
Correspondence to Hiroaki Matsubara, MD, Department of Medicine II, Kansai Medical University, Fumizonocho 10-15, Moriguchi, Osaka 570-8507, Japan. E-mail matsubah{at}takii.kmu.ac.jp
Abstract—Since the discovery of nonpeptidic ligands, the receptors for angiotensin (Ang) II have been classified into 2 subtypes (Ang II type 1 receptor [AT1-R] and Ang II type 2 receptor [AT2-R]). AT1-R mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetus. Its expression is very low in the cardiovascular system of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or inflammation. In failing hearts or neointima formation after vascular injury, AT2-R is reexpressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT2-R. Cardiac myocyte- or vascular smooth muscle–specific mice that overexpress AT2-R display an inhibition of Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells and the maintenance of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal systems, resulting in AT2-R–mediated cardioprotection, vasodilation, and pressure natriuresis. These effects, transmitted by AT2-R, are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in a Gi protein–dependent manner. The expression level of AT2-R is much higher in human hearts than in rodent hearts, and the AT2-R–mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists. Thus, in this review, the regulation of AT2-R expression, its cellular localization, its pathological role in cardiovascular and kidney diseases, and pharmacotherapeutic effects of AT2-R stimulation are discussed.
Key Words: angiotensin II receptor • angiotensin II type 2 receptor • angiotensin II AT2 receptor • angiotensin II type 1 receptor • angiotensin II AT1 receptor
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A. Goette, U. Lendeckel, and H. U Klein Signal transduction systems and atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 247 - 258. [Abstract] [Full Text] [PDF]
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 R. Ferrari, G. Guardigli, G. Cicchitelli, M. Valgimigli, E. Merli, O. Soukhomorskaia, and C. Ceconi Angiotensin II overproduction: enemy of the vessel wall Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A26 - A30. [Abstract] [PDF]
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L. Wu, M. Iwai, H. Nakagami, R. Chen, J. Suzuki, M. Akishita, M. de Gasparo, and M. Horiuchi Effect of Angiotensin II Type 1 Receptor Blockade on Cardiac Remodeling in Angiotensin II Type 2 Receptor Null Mice Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 49 - 54. [Abstract] [Full Text] [PDF]
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 B. Badzynska, M. Grzelec-Mojzesowicz, L. Dobrowolski, and J. Sadowski Differential effect of angiotensin II on blood circulation in the renal medulla and cortex of anaesthetised rats J. Physiol., January 1, 2002; 538(1): 159 - 166. [Abstract] [Full Text] [PDF]
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Y. Kansui, K. Fujii, K. Goto, and I. Abe Bradykinin Enhances Sympathetic Neurotransmission in Rat Blood Vessels Hypertension, January 1, 2002; 39(1): 29 - 34. [Abstract] [Full Text] [PDF]
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J. L. Segar, G. B. Dalshaug, K. A. Bedell, O. M. Smith, and T. D. Scholz Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2037 - R2047. [Abstract] [Full Text] [PDF]
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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]
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M. P. Schuijt, M. Basdew, R. van Veghel, R. de Vries, P. R. Saxena, R. G. Schoemaker, and A. H. Jan Danser AT2 receptor-mediated vasodilation in the heart: effect of myocardial infarction Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2590 - H2596. [Abstract] [Full Text] [PDF]
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J. Deinum, J. M.G. van Gool, M. J.M. Kofflard, F. J. ten Cate, and A.H. J. Danser Angiotensin II Type 2 Receptors and Cardiac Hypertrophy in Women With Hypertrophic Cardiomyopathy Hypertension, December 1, 2001; 38(6): 1278 - 1281. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, V. Esteban, Y. Suzuki, S. Mezzano, J.J. Plaza, and J. Egido Role of the Renin-Angiotensin System in Vascular Diseases: Expanding the Field Hypertension, December 1, 2001; 38(6): 1382 - 1387. [Abstract] [Full Text] [PDF]
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Y. Suzuki, O. Lopez-Franco, D. Gomez-Garre, N. Tejera, C. Gomez-Guerrero, T. Sugaya, R. Bernal, J. Blanco, L. Ortega, and J. Egido Renal Tubulointerstitial Damage Caused by Persistent Proteinuria Is Attenuated in AT1-Deficient Mice : Role of Endothelin-1 Am. J. Pathol., November 1, 2001; 159(5): 1895 - 1904. [Abstract] [Full Text] [PDF]
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D. Henrion, N. Kubis, and B. I. Levy Physiological and Pathophysiological Functions of the AT2 Subtype Receptor of Angiotensin II: From Large Arteries to the Microcirculation Hypertension, November 1, 2001; 38(5): 1150 - 1157. [Abstract] [Full Text] [PDF]
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C.-M. Yu, G. L. Tipoe, K. Wing-Hon Lai, and C.-P. Lau Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1207 - 1215. [Abstract] [Full Text] [PDF]
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Y. Shibasaki, H. Matsubara, Y. Nozawa, Y. Mori, H. Masaki, A. Kosaki, Y. Tsutsumi, Y. Uchiyama, S. Fujiyama, A. Nose, et al. Angiotensin II Type 2 Receptor Inhibits Epidermal Growth Factor Receptor Transactivation by Increasing Association of SHP-1 Tyrosine Phosphatase Hypertension, September 1, 2001; 38(3): 367 - 372. [Abstract] [Full Text] [PDF]
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S. Sanada, M. Kitakaze, K. Node, S. Takashima, A. Ogai, H. Asanuma, Y. Sakata, M. Asakura, H. Ogita, Y. Liao, et al. Differential Subcellular Actions of ACE Inhibitors and AT1 Receptor Antagonists on Cardiac Remodeling Induced by Chronic Inhibition of NO Synthesis in Rats Hypertension, September 1, 2001; 38(3): 404 - 411. [Abstract] [Full Text] [PDF]
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S. A. Mezzano, M. Ruiz-Ortega, and J. Egido Angiotensin II and Renal Fibrosis Hypertension, September 1, 2001; 38(3): 635 - 638. [Abstract] [Full Text] [PDF]
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S. Lee, C. M. Kramer, S. Mankad, S.-e. Yoo, and K. Sandberg Combined angiotensin converting enzyme inhibition and angiotensin AT1 receptor blockade up-regulates myocardial AT2 receptors in remodeled myocardium post-infarction Cardiovasc Res, July 1, 2001; 51(1): 131 - 139. [Abstract] [Full Text] [PDF]
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H. Matsubara Renin-Angiotensin System in Human Failing Hearts : Message From Nonmyocyte Cells to Myocytes Circ. Res., May 11, 2001; 88(9): 861 - 863. [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, J. Blanco, and J. Egido Systemic Infusion of Angiotensin II into Normal Rats Activates Nuclear Factor-{{kappa}}B and AP-1 in the Kidney : Role of AT1 and AT2 Receptors Am. J. Pathol., May 1, 2001; 158(5): 1743 - 1756. [Abstract] [Full Text] [PDF]
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L. H. Opie and M. N. Sack Enhanced Angiotensin II Activity in Heart Failure : Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes Circ. Res., April 13, 2001; 88(7): 654 - 658. [Abstract] [Full Text] [PDF]
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 A. Otani, H. Takagi, H. Oh, S. Koyama, and Y. Honda Angiotensin II Induces Expression of the Tie2 Receptor Ligand, Angiopoietin-2, in Bovine Retinal Endothelial Cells Diabetes, April 1, 2001; 50(4): 867 - 875. [Abstract] [Full Text]
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S. Fujiyama, H. Matsubara, Y. Nozawa, K. Maruyama, Y. Mori, Y. Tsutsumi, H. Masaki, Y. Uchiyama, Y. Koyama, A. Nose, et al. Angiotensin AT1 and AT2 Receptors Differentially Regulate Angiopoietin-2 and Vascular Endothelial Growth Factor Expression and Angiogenesis by Modulating Heparin Binding-Epidermal Growth Factor (EGF)-Mediated EGF Receptor Transactivation Circ. Res., January 19, 2001; 88(1): 22 - 29. [Abstract] [Full Text] [PDF]
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S. G. Myerson, H. E. Montgomery, M. Whittingham, M. Jubb, M. J. World, S. E. Humphries, and D. J. Pennell Left Ventricular Hypertrophy With Exercise and ACE Gene Insertion/Deletion Polymorphism : A Randomized Controlled Trial With Losartan Circulation, January 16, 2001; 103(2): 226 - 230. [Abstract] [Full Text] [PDF]
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S. Kim, M. Yoshiyama, Y. Izumi, H. Kawano, M. Kimoto, Y. Zhan, and H. Iwao Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure Circulation, January 2, 2001; 103(1): 148 - 154. [Abstract] [Full Text] [PDF]
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S. L. Malendowicz, P. V. Ennezat, M. Testa, L. Murray, E. H. Sonnenblick, T. Evans, and T. H. LeJemtel Angiotensin II Receptor Subtypes in the Skeletal Muscle Vasculature of Patients With Severe Congestive Heart Failure Circulation, October 31, 2000; 102(18): 2210 - 2213. [Abstract] [Full Text] [PDF]
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J. L. Hansen, G. Servant, T. J. Baranski, T. Fujita, T. Iiri, and S. P. Sheikh Functional Reconstitution of the Angiotensin II Type 2 Receptor and Gi Activation Circ. Res., October 27, 2000; 87(9): 753 - 759. [Abstract] [Full Text] [PDF]
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A. J. Allred, M. C. Chappell, C. M. Ferrario, and D. I. Diz Differential actions of renal ischemic injury on the intrarenal angiotensin system Am J Physiol Renal Physiol, October 1, 2000; 279(4): F636 - F645. [Abstract] [Full Text] [PDF]
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Y. Xu, A. S. Clanachan, and B. I. Jugdutt Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C{epsilon} During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade Hypertension, October 1, 2000; 36(4): 506 - 510. [Abstract] [Full Text] [PDF]
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K. Goto, K. Fujii, U. Onaka, I. Abe, and M. Fujishima Renin-Angiotensin System Blockade Improves Endothelial Dysfunction in Hypertension Hypertension, October 1, 2000; 36(4): 575 - 580. [Abstract] [Full Text] [PDF]
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J. P. van Kats, D. J. Duncker, D. B. Haitsma, M. P. Schuijt, R. Niebuur, R. Stubenitsky, F. Boomsma, M. A. D. H. Schalekamp, P. D. Verdouw, and A. H. J. Danser Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling in Pigs After Myocardial Infarction : Role of Tissue Angiotensin II Circulation, September 26, 2000; 102(13): 1556 - 1563. [Abstract] [Full Text] [PDF]
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 M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger International Union of Pharmacology. XXIII. The Angiotensin II Receptors Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472. [Abstract] [Full Text] [PDF]
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J. Sadoshima Cytokine Actions of Angiotensin II Circ. Res., June 23, 2000; 86(12): 1187 - 1189. [Full Text] [PDF]
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