The angiotensin AT 2 receptor (AT2R) represents an important component of the renin-angiotensin system since it is involved in the (patho) physiology of different cardiovascular and neuronal diseases. Furthermore, AT2 receptors can partly mediate beneficial effects of angiotensin AT 1 receptor (AT1R) blockers, and direct pharmacological AT 2 receptor agonism emerges as a novel therapeutic strategy. This review discusses the constitutive and ligand-mediated activity as well as the signal transduction of the AT2 receptor, focusing on adapter proteins which directly bind to this receptor. Direct protein-protein interaction partners of the AT2 receptor described so far include the transcription factor promyelocytic zinc finger protein, AT2 receptor binding protein and the AT1 receptor. In addition, the putative crosstalk of the AT2 receptor with the renin/ prorenin receptor (RER) via the promyelocytic zinc finger protein (PLZF) and the role of oestrogens on the regulation of the AT2 receptor are presented. Conceiving the coupling of the AT2 receptor to different adapter proteins with distinct and partly opposing cellular effects and the implications of its constitutive activity might help to overcome the current controversies on the (patho)physiological role of the AT2 receptor.
de Gasparo M. , Catt KJ, Inagami T. et al. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev2000;52:415-72.
2.
Kaschina E. , Unger T.Angiotensin AT1/AT2 receptors: regulation, signalling and function. Blood Press2003 ;12:70-88.
3.
Unger T.The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol2002;89:3A-9A; discussion 10A.
4.
Lindberg H. , Nielsen D., Jensen BV et al. Angiotensin converting enzyme inhibitors for cancer treatment?Acta Oncol2004;43:142-52.
5.
Ruiz-Ortega M. , Lorenzo O., Ruperez M. et al. Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension2001;38:1382-7.
6.
Weiss D., Sorescu D., Taylor WRAngiotensin II and atherosclerosis. Am J Cardiol2001;87:25C-32C.
7.
Sleight P.Angiotensin II and trials of cardiovascular outcomes. Am J Cardiol2002;89:11A-16A; discussion 16A-17A.
8.
Stoll M., Steckelings UM, Paul M. et al. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest1995;95:651-7.
9.
Volpe M., Musumeci B., De Paolis P. et al. Angiotensin II AT2 receptor subtype: an uprising frontier in cardiovascular disease?J Hypertens2003;21:1429-43.
10.
Meffert S., Stoll M., Steckelings UM et al. The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol Cell Endocrinol1996;122:59-67.
11.
Stroth U., Blume A., Mielke K. et al. Angiotensin AT(2) receptor stimulates ERK1 and ERK2 in quiescent but inhibits ERK in NGF-stimulated PC12W cells. Brain Res Mol Brain Res2000;78:175-80.
12.
Li J., Culman J., Hortnagl H. et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J2005;19:617-19.
13.
Lucius R., Gallinat S., Rosenstiel P. et al. The angiotensin II type 2 (AT2) receptor promotes axonal regeneration in the optic nerve of adult rats. J Exp Med1998;188:661-70.
14.
Reinecke K. , Lucius R., Reinecke A. et al. Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB. FASEB J2003 ;17:2094-6.
15.
Brown MJAliskiren. Circulation2008;118:773-84.
16.
Nguyen G., Delarue F., Burckle C. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest2002;109:1417-27.
17.
Ichihara A. , Kaneshiro Y., Takemitsu T. et al. Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension2006; 47:894-900.
18.
Ichihara A. , Hayashi M., Kaneshiro Y. et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. J Clin Invest2004 ;114:1128-35.
19.
Widdop RE, Jones ES, Hannan RE et al. Angiotensin AT2 receptors: cardiovascular hope or hype?Br J Pharmacol2003;140:809-24.
20.
Levy BICan angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system . Circulation2004;109:8-13.
21.
Berk BCAngiotensin type 2 receptor (AT2R): a challenging twin. Sci STKE2003;2003:PE16.
22.
Rang HP, Dale MM, Ritter JM, Moore PK (eds.). Pharmacology. Edinburgh: Churchill Livingstone, 2003.
23.
Seifert R., Wenzel-Seifert K.Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch Pharmacol2002;366:381-416.
24.
Miura S., Karnik SSAngiotensin II type 1 and type 2 receptors bind angiotensin II through different types of epitope recognition. J Hypertens1999;17:397-404.
25.
Miura S., Karnik SSLigand-independent signals from angiotensin II type 2 receptor induce apoptosis . EMBO J2000;19:4026-35.
26.
Horiuchi M. , Koike G., Yamada T. et al. The growth-dependent expression of angiotensin II type 2 receptor is regulated by transcription factors interferon regulatory factor-1 and -2. J Biol Chem1995 ;270:20225-30.
27.
Cresci B., Giannini S., Pala L. et al. AT1 and AT2 receptors in human glomerular endothelial cells at different passages. Microvasc Res2003;66:22-9.
28.
Unpublished data.
29.
D’Amore A., Black MJ, Thomas WGThe angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor-mediated hypertrophy. Hypertension2005;46:1347-54.
30.
Miura S., Karnik SS, Saku K.Constitutively active homo-oligomeric angiotensin II type 2 receptor induces cell signaling independent of receptor conformation and ligand stimulation . J Biol Chem2005;280:18237-44.
31.
Landon EJ, Inagami T.Beyond the G protein: the saga of the type 2 angiotensin II receptor . Arterioscler Thromb Vasc Biol2005
32.
Senbonmatsu T., Saito T., Landon EJ et al. A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy . EMBO J2003;22:6471-82.
33.
Csikos T., Balmforth AJ, Grojec M. et al. Angiotensin AT2 receptor degradation is prevented by ligand occupation . Biochem Biophys Res Commun1998;243:142-7.
34.
Zhang J., Pratt REThe AT2 receptor selectively associates with Gialpha2 and Gialpha3 in the rat fetus. J Biol Chem1996;271:15026-33.
35.
Hansen JL, Servant G., Baranski TJ et al. Functional reconstitution of the angiotensin II type 2 receptor and G(i) activation. Circ Res2000;87:753-9.
36.
Schefe JH, Menk M., Reinemund J. et al. A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circ Res2006;99:1355-66.
37.
Costoya JA, Pandolfi PPThe role of promyelocytic leukemia zinc finger and promyelocytic leukemia in leukemogenesis and development. Curr Opin Hematol2001;8:212-17.
38.
Feng YH, Sun Y., Douglas JGGbeta gamma -independent constitutive association of Galpha s with SHP-1 and angiotensin II receptor AT2 is essential in AT2-mediated ITIM-independent activation of SHP-1. Proc Natl Acad Sci U S A2002;99:12049-54.
39.
Wruck CJ, Funke-Kaiser H., Pufe T. et al. Regulation of transport of the angiotensin AT2 receptor by a novel membrane-associated Golgi protein. Arterioscler Thromb Vasc Biol2005;25:57-64.
40.
Nouet S., Amzallag N., Li JM et al. Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. J Biol Chem2004;279:28989-97.
41.
Di Benedetto M., Bieche I., Deshayes F. et al. Structural organization and expression of human MTUS1, a candidate 8p22 tumor suppressor gene encoding a family of angiotensin II AT2 receptor-interacting proteins, ATIP. Gene2006;380:127-36.
42.
Seibold S., Rudroff C., Weber M. et al. Identification of a new tumor suppressor gene located at chromosome 8p21.3-22. FASEB J2003;17:1180-2.
43.
de Godoy MA , Rattan S.Translocation of AT1- and AT2-receptors by higher concentrations of angiotensin II in the smooth muscle cells of rat internal anal sphincter. J Pharmacol Exp Ther2006;319:1088-95.
44.
Stoll M., Hahn AW, Jonas U. et al. Identification of a zinc finger homoeodomain enhancer protein after AT(2) receptor stimulation by differential mRNA display. Arterioscler Thromb Vasc Biol2002;22:231-7.
45.
Gohlke P., Pees C., Unger T.AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension1998 ;31:349-55.
46.
Carey RMUpdate on the role of the AT2 receptor. Curr Opin Nephrol Hypertens2005;14:67-71.
Gallinat S. , Busche S., Schutze S. et al. AT2 receptor stimulation induces generation of ceramides in PC12W cells. FEBS Lett1999 ;443:75-9.
49.
Nguyen G., Burckle CA, Sraer JDRenin/prorenin-receptor biochemistry and functional significance. Curr Hypertens Rep2004;6:129-32.
50.
Shioi T., Kang PM, Douglas PS et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J2000;19:2537-48.
51.
Schefe JH, Neumann C., Goebel M. et al. Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren. J Hypertens2008; 26:1787-94.
52.
Ichihara A. , Kaneshiro Y., Takemitsu T. et al. Receptor-associated prorenin system contributes to hypertensive end-organ damage. J Hypertens2005;23(suppl 2):S78;P1.197.
53.
Ichihara A. , Suzuki F., Nakagawa T. et al. Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol2006;17:1950-61.
54.
Susic D., Zhou X., Frohlich ED et al. Cardiovascular effects of prorenin blockade in genetically spontaneously hypertensive rats on normal and high-salt diet. Am J Physiol Heart Circ Physiol2008;295:H1117-21.
55.
Shibata K., Makino I., Shibaguchi H. et al. Up-regulation of angiotensin type 2 receptor mRNA by angiotensin II in rat cortical cells. Biochem Biophys Res Commun1997;239:633-7.
56.
Tanaka M., Tsuchida S., Imai T. et al. Vascular response to angiotensin II is exaggerated through an upregulation of AT1 receptor in AT2 knockout mice. Biochem Biophys Res Commun1999;258:194-8.
57.
Jin XQ, Fukuda N., Su JZ et al. Angiotensin II type 2 receptor gene transfer downregulates angiotensin II type 1a receptor in vascular smooth muscle cells. Hypertension2002;39:1021-7.
58.
De Paolis P. , Porcellini A., Gigante B. et al. Modulation of the AT2 subtype receptor gene activation and expression by the AT1 receptor in endothelial cells. J Hypertens1999;17:1873-7.
59.
Liu YH, Yang XP, Sharov VG et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest1997;99:1926-35.
60.
Wu L., Iwai M., Nakagami H. et al. Effect of angiotensin II type 1 receptor blockade on cardiac remodeling in angiotensin II type 2 receptor null mice. Arterioscler Thromb Vasc Biol2002;22:49-54.
61.
Xu J., Carretero OA, Liu YH et al. Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension2002;40:244-50.
62.
Sandmann S. , Yu M., Kaschina E. et al. Differential effects of angiotensin AT1 and AT2 receptors on the expression, translation and function of the Na+-H+ exchanger and Na+-HCO3- symporter in the rat heart after myocardial infarction . J Am Coll Cardiol2001;37:2154-65.
63.
Hein L., Barsh GS, Pratt RE et al. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature1995;377:744-7.
64.
Ichiki T., Labosky PA, Shiota C. et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature1995 ;377:748-50.
65.
Tsutsumi Y. , Matsubara H., Masaki H. et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest1999;104:925-35.
66.
Moore AF, Heiderstadt NT, Huang E. et al. Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats. Hypertension2001;37:1285-91.
67.
Munzenmaier DH, Greene ASOpposing actions of angiotensin II on microvascular growth and arterial blood pressure. Hypertension1996;27:760-5.
68.
Duke LM, Evans RG, Widdop REAT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats. Am J Physiol Heart Circ Physiol2005 ; 288:H2289-97.
69.
Phoon S., Howes LGForearm vasodilator response to angiotensin II in elderly women receiving candesartan: role of AT(2)- receptors. J Renin Angiotensin Aldosterone Syst2002;3:36-9.
70.
Mendelsohn ME, Karas RHThe protective effects of estrogen on the cardiovascular system. N Engl J Med1999; 340:1801-11.
71.
Mendelsohn ME, Karas RHMolecular and cellular basis of cardiovascular gender differences. Science2005;308:1583-7.
72.
Armando I., Jezova M., Juorio AV et al. Estrogen upregulates renal angiotensin II AT(2) receptors. Am J Physiol Renal Physiol2002;283:F934-43.
73.
Suarez C., Diaz-Torga G., Gonzalez-Iglesias A. et al. Upregulation of angiotensin II type 2 receptor expression in estrogen-induced pituitary hyperplasia. Am J Physiol Endocrinol Metab2004;286:E786-94.
74.
Dean SA, Tan J., O’Brien ER et al. 17beta-estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats. Am J Physiol Regul Integr Comp Physiol2005;288:R759-66.
75.
Deinum J., van Gool JM, Kofflard MJ et al. Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy. Hypertension2001;38:1278-81.
76.
Jin JJ, Nakura J., Wu Z. et al. Association of angiotensin II type 2 receptor gene variant with hypertension. Hypertens Res2003;26:547-52.
77.
Reinemund J. , Steckelings UM, Seidel K. et al. Manuscript in preparation.
78.
Ju BG, Lunyak VV, Perissi V. et al. A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science2006;312:1798-802.
79.
Lis JT, Kraus WLPromoter cleavage: a topoIIbeta and PARP-1 collaboration. Cell2006;125:1225-7.
80.
Ziegler M., Oei SLA cellular survival switch: poly(ADPribosyl)ation stimulates DNA repair and silences transcription. Bioessays2001 ;23:543-8.
81.
D’Amours D., Desnoyers S., D’Silva I. et al. Poly(ADPribosyl)ation reactions in the regulation of nuclear functions. Biochem J1999;342:249-68.
Love S., Barber R., Wilcock GKIncreased poly(ADPribosyl)ation of nuclear proteins in Alzheimer’s disease . Brain1999;122:247-53.
84.
Luft FCSomatic DNA oxidative damage and coronary disease. J Mol Med2005;83:241-3.
85.
Jagtap P., Szabo C.Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors . Nat Rev Drug Discov2005;4:421-40.
86.
Kim MY, Zhang T., Kraus WLPoly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal. Genes Dev2005;19:1951-67.
87.
Meisterernst M., Stelzer G., Roeder RGPoly(ADP-ribose) polymerase enhances activator-dependent transcription in vitro. Proc Natl Acad Sci U S A1997;94:2261-5.
88.
Chiba-Falek O., Kowalak JA, Smulson ME et al. Regulation of alpha-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. Am J Hum Genet2005;76:478-92.
89.
Simbulan-Rosenthal CM, Ly DH, Rosenthal DS et al. Misregulation of gene expression in primary fibroblasts lacking poly(ADP-ribose) polymerase . Proc Natl Acad Sci U S A2000;97:11274-9.
90.
Slattery E. , Dignam JD, Matsui T. et al. Purification and analysis of a factor which suppresses nick-induced transcription by RNA polymerase II and its identity with poly(ADPribose) polymerase . J Biol Chem1983; 258:5955-9.
91.
Szabo C., Pacher P., Zsengeller Z. et al. Angiotensin IImediated endothelial dysfunction: role of poly(ADP-ribose) polymerase activation. Mol Med2004;10:28-35.
92.
Pillai JB, Gupta M., Rajamohan SB et al. Poly(ADPribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol2006;291:H1545-53.
93.
Molnar A., Toth A., Bagi Z. et al. Activation of the poly(ADP-ribose) polymerase pathway in human heart failure. Mol Med2006;12:143-52.
94.
http://clinicaltrials.gov (accessed May 2008).
95.
Yang Z., Bove CM, French BA et al. Angiotensin II type 2 receptor overexpression preserves left ventricular function after myocardial infarction. Circulation2002;106:106-11.
96.
Metcalfe BL , Huentelman MJ, Parilak LD et al. Prevention of cardiac hypertrophy by angiotensin II type-2 receptor gene transfer. Hypertension2004;43:1233-8.
97.
Falcon BL, Stewart JM, Bourassa E. et al. Angiotensin II type 2 receptor gene transfer elicits cardioprotective effects in an angiotensin II infusion rat model of hypertension. Physiol Genomics2004;19:255-61.
98.
Kaschina E. , Grzesiak A., Li JM et al. AT2-receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin-system in myocardial infarction?Circulation2008 ;(In press).
99.
Busche S., Gallinat S., Bohle RM et al. Expression of angiotensin AT(1) and AT(2) receptors in adult rat cardiomyocytes after myocardial infarction. A single-cell reverse transcriptasepolymerase chain reaction study. Am J Pathol2000;157:605-11.
100.
Mifune M., Sasamura H., Shimizu-Hirota R. et al. Angiotensin II type 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells. Hypertension2000; 36:845-50.
101.
Levy BI, Benessiano J., Henrion D. et al. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest1996;98:418-25.
102.
Senbonmatsu T., Ichihara S., Price E., Jr. et al. Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte ) enlargement during in vivo pressure overload. J Clin Invest2000;106:R1-5.
103.
Ichihara S. , Senbonmatsu T., Price E., Jr. et al. Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation2001;104:346-51.
104.
Kurisu S., Ozono R., Oshima T. et al. Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension2003;41:99-107.
105.
Sugino H., Ozono R., Kurisu S. et al. Apoptosis is not increased in myocardium overexpressing type 2 angiotensin II receptor in transgenic mice. Hypertension2001;37:1394-8.
106.
Batenburg WW, Garrelds IM, Bernasconi CC et al. Angiotensin II type 2 receptor-mediated vasodilation in human coronary microarteries. Circulation2004;109:2296-301.
107.
Steckelings UM, Henz, BM, Wiehstutz S. et al. Differential expression of angiotensin receptors in human cutaneous wound healing. Brit J Dermatol2005;153:887-93.
108.
Wharton J. , Morgan K., Rutherford RA et al. Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. J Pharmacol Exp Ther1998;284:323-36.
109.
Shaknovich R., Yeyati PL, Ivins S. et al. The promyelocytic leukemia zinc finger protein affects myeloid cell growth, differentiation, and apoptosis. Mol Cell Biol1998;18:5533-45.
110.
AbdAlla S. , Lother H., Abdel-tawab AM et al. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem2001 ;276:39721-6.
111.
Jones ES, Vinh A., McCarthy CA et al. AT(2) receptors: functional relevance in cardiovascular disease . Pharmacol Ther2008;120:292-316.
112.
Kenakin T.Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends Pharmacol Sci1995;16:232-8.
113.
Rajagopal K., Lefkowitz RJ, Rockman HAWhen 7 transmembrane receptors are not G protein-coupled receptors. J Clin Invest2005;115:2971-4.
114.
Wan Y. , Wallinder C., Plouffe B. et al. Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist . J Med Chem2004;47:5995-6008.
115.
Ontarget Investigators.Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med2008;358:1547-59.
116.
Sealey JE, Laragh JHAliskiren fails to lower blood pressure in patients who have either low PRA levels or whose PRA falls insufficiently or reactively rises. Am J Hypertens2009;22:112-21.
