Proteinase-activated Receptor 2 (PAR2): A challenging new target for treatment of vascular diseases

Current Pharmaceutical Design

Volumn 10, Issue 22, 2004, Pages 2769-2778

  McGuire, John J ^a  

^a MEMORIAL UNIVERSITY OF NEWFOUNDLAND   (Canada)

Author keywords

Atherosclerosis; Blood pressure; EDHF; Endothelium; Hyperpolarization; Hypertension; Inflammation; Nitric oxide; PAR 2; PAR2; Protease activated receptor 2; Proteinase activated Receptor 2; Vascular smooth muscle

Indexed keywords

ENZYME ACTIVATOR; GLYCERYL TRINITRATE; NITRIC OXIDE; PROSTAGLANDIN SYNTHASE; PROTEINASE ACTIVATED RECEPTOR 1; PROTEINASE ACTIVATED RECEPTOR 2; PROTEINASE ACTIVATED RECEPTOR 2 AGONIST; PROTEINASE ACTIVATED RECEPTOR 2 ANTAGONIST; PROTEINASE ACTIVATED RECEPTOR 3; PROTEINASE ACTIVATED RECEPTOR 4; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; SILDENAFIL; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; BLOOD FLOW; BLOOD VESSEL TONE; CARDIOVASCULAR DISEASE; CELL CULTURE; DISEASE COURSE; DRUG DESIGN; DRUG MECHANISM; DRUG SELECTIVITY; DRUG TARGETING; ENZYME ACTIVATION; HUMAN; HYPERPOLARIZATION; MALIGNANT NEOPLASTIC DISEASE; MEDICAL RESEARCH; MOUSE; NONHUMAN; PARACRINE SIGNALING; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SMOOTH MUSCLE FIBER; TRANSGENIC MOUSE; UNSTABLE ANGINA PECTORIS; VASCULAR DISEASE; VASCULAR ENDOTHELIUM; VASCULAR SMOOTH MUSCLE; VASODILATATION;

ANIMALS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; MODELS, BIOLOGICAL; RECEPTOR, PAR-2; VASCULAR DISEASES;

EID: 4344638935     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612043383656     Document Type: Review

References (88)

1. Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R. Proteinase-activated receptors. Pharmacol Rev 2001; 53: 245-82.
2. Hollenberg MD, Compton SJ. International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev 2002; 54: 203-17.
3. Camerer E, Kataoka H, Kahn M, Lease K, Coughlin SR. Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells. J Biol Chem 2002; 277: 16081-7.
4. Riewald M, Ruf W. Orchestration of coagulation protease signaling by tissue factor. Trends Cardiovasc; Med 2002; 12: 149-54.
5. Nystedt S, Larsson AK, Aberg H, Sundelin J. The mouse proteinase-activated receptor-2 cDNA and gene. Molecular cloning and functional expression. J Biol Chem 1995; 270: 5950-5.
6. Cottrell GS, Amadesi S, Grady EF, Bunnett NW. Trypsin IV: A novel agonist of protease-activated receptors 2 and 4. J Biol Chem 2004; 279: 13532-9.
7. Brass LF, Molino M. Protease-activated G protein-coupled receptors on human platelets and endothelial cells. Thromb Haemost 1997; 78: 234-41.
8. Uehara A, Sugawara S, Muramoto K, Takada H. Activation of human oral epithelia cells by neutrophil proteinase 3 through protease-activated receptor-2. J Immunol 2002; 169: 4594-603.
9. Takeuchi T, Harris JL, Huang W, Yan KW, Coughlin SR, Craik CS. Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. J Biol Chem 2000; 275: 26333-42.
10. Milia AF, Salis MB, Stacca T, Pinna A, Madeddu P, Trevisani M. et al. Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia. Circ Res 2002; 91: 346-52.
11. McGuire JJ, Saifeddine M, Triggle CR, Sun K, Hollenberg MD. 2-furoyl-LIGRLO-amide: A potent and selective Proteinase-Activated Receptor 2 (PAR-2) agonist. J Pharmacol Exp Ther 2004; 309: 1124-31. PMID: 14976230.
12. Kawabata A, Kanke T, Yonezawa D, Ishiki T, Saka M, Kabeya M, et al. Potent and Metabolically Stable Agonists for Protease-Activated Receptor-2: Evaluation of Activity in Multiple Assay Systems In Vitro and In Vivo. J Pharmacol Exp Ther 2004; 309: 1098-107. PMID: 14976227.
13. Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE, et al. Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest 2003; 111: 35-41.
14. McGuire JJ, Dai J, Andrade-Gordon P, Triggle CR, Hollenberg MD. Proteinase-activated receptor-2 (PAR2): vascular effects of a PAR2-derived activating peptide via a receptor different than PAR2. J Pharmacol Exp Ther 2002; 303: 985-92.
15. Stenton GR, Nohara O, Dery RE, Vliagoftis H, Gilchrist M, Johri A, et al. Proteinase-activated receptor (PAR)-1 and -2 agonists induce mediator release from mast cells by pathways distinct from PAR-1 and PAR-2. J Pharmacol Exp Ther 2002; 302: 466-74.
16. Trejo J. Protease Activated Receptors: New Concepts in Regulation of G-Protein-Coupled Receptor Signaling and Trafficking. J Pharmacol Exp Ther 2003; 307: 437-42.
17. Major CD, Santulli RJ, Derian CK, Andrade-Gordon P. Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice. Arterioscler Thromb Vasc Biol 2003; 23: 931-9.
18. Derian CK, Maryanoff BE, Zhang HC, Andrade-Gordon P. Therapeutic potential of protease-activated receptor-1 antagonists. Expert Opin Investig Drugs 2003; 12: 209-21.
19. Derian CK, Damiano BP, Addo MF, Darrow AL, D'Andrea MR, Nedelman M, et al. Blockade of the thrombin receptor protease-activated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates. J Pharmacol Exp Ther 2003; 304: 855-61.
20. Cenac N, Coelho AM, Nguyen C, Compton S, Andrade-Gordon P, MacNaughton WK, et al. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am J Pathol 2002; 161: 1903-15.
21. Schmidlin F, Amadesi S, Dabbagh K, Lewis DE, Knott P, Bunnett NW, et al. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol 2002; 169: 5315-21.
22. Lindner JR, Kahn ML, Coughlin SR, Sambrano GR, Schauble E, Bernstein D, et al. Delayed onset of inflammation in protease-activated receptor-2-deficient mice. J Immunol 2000; 165: 6504-10.
23. Seeliger S, Derian CK, Vergnolle N, Bunnett NW, Nawroth R, Schmelz M, et al. Proinflammatory role of proteinase-activated receptor-2 in humans and mice during cutaneous inflammation in vivo. FASEB J 2003; 17: 1871-85.
24. Pawlinski R, Pedersen B, Schabbauer G, Tencati M, Holscher T, Boisvert W, et al. Role of tissue factor and protease activated receptors in a mouse model of endotoxemia. Blood 2004; 103:1342-1347.
25. Hollenberg MD, Saifeddine M, Al Ani B. Proteinase-activated receptor-2 in rat aorta: structural requirements for agonist activity of receptor-activating peptides. Mol Pharmacol 1996; 49: 229-33.
26. Moffatt JD, Cocks TM. Endothelium-dependent and -independent responses to protease-activated receptor-2 (PAR-2) activation in mouse isolated renal arteries. Br J Pharmacol 1998; 125: 591-4.
27. Sobey CG, Cocks TM. Activation of protease-activated receptor-2 (PAR-2) elicits nitric oxide-dependent dilatation of the basilar artery in vivo. Stroke 1998; 29: 1439-44.
28. Glusa E, Saft A, Prasa D, Sturzebecher J. Trypsin- and SLIGRL-induced vascular relaxation and the inhibition by benzamidine derivatives. Thromb Haemost 1997; 78: 1399-403.
29. Magazine HI, King JM, Srivastava KD. Protease activated receptors modulate aortic vascular tone. Int J Cardiol 1996; 53: Suppl-80.
30. Al Ani B, Saifeddine M, Hollenberg MD. Detection of functional receptors for the proteinase-activated-receptor-2-activating polypeptide, SLIGRL-NH2, in rat vascular and gastric smooth muscle. Can J Physiol Pharmacol 1995; 73: 1203-7.
31. Cicala C. Protease activated receptor 2 and the cardiovascular system. Br J Pharmacol 2002; 135: 14-20.
32. Hamilton JR, Frauman AG, Cocks TM. Increased expression of protease-activated receptor-2 (PAR2) and PAR4 in human coronary artery by inflammatory stimuli unveils endothelium-dependent relaxations to PAR2 and PAR4 agonists. Circ Res 2001; 89: 92-8.
33. Hamilton JR, Moffatt JD, Tatoulis J, Cocks TM. Enzymatic activation of endothelial protease-activated receptors is dependent on artery diameter in human and porcine isolated coronary arteries. Br J Pharmacol 2002; 136: 492-501.
34. Damiano BP, Cheung WM, Santulli RJ, Fung-Leung WP, Ngo K, Ye RD, et al. Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1. J Pharmacol Exp Ther 1999; 288: 671-8.
35. Emilsson K, Wahlestedt C, Sun MK, Nystedt S, Owman C, Sundelin J. Vascular effects of proteinase-activated receptor 2 agonist peptide. J Vasc Res 1997; 34: 267-72.
36. Robin J, Kharbanda R, Mclean P, Campbell R, Vallance P. Protease-activated receptor 2-mediated vasodilatation in humans in vivo: role of nitric oxide and prostanoids. Circulation 2003; 107: 954-9.
37. Trottier G, Hollenberg M, Wang X, Gui Y, Loutzenhiser K, Loutzenhiser R. PAR-2 elicits afferent arteriolar vasodilation by NO-dependent and NO-independent actions. Am J Physiol Renal Physiol 2002; 282: F891-F897.
38. Kawabata A, Kubo S, Nakaya Y, Ishiki T, Kuroda R, Sekiguchi F, et al. Distinct roles for protease-activated receptors 1 and 2 in vasomotor modulation in rat superior mesenteric artery. Cardiovasc Res 2004; 61: 683-92.
39. Vanhoutte PM. Endothelium-dependent hyperpolarizations: the history. Pharmacol Res 2004; 49: 503-8.
40. Kawabata A, Nakaya Y, Kuroda R, Wakisaka M, Masuko T, Nishikawa H, et al. Involvement of EDHF in the hypotension and increased gastric mucosal blood flow caused by PAR-2 activation in rats. Br J Pharmacol 2003; 140: 247-54.
41. McGuire JJ, Hollenberg MD, Andrade-Gordon P, Triggle CR. Multiple mechanisms of vascular smooth muscle relaxation by the activation of proteinase-activated receptor 2 in mouse mesenteric arterioles. Br J Pharmacol 2002; 135: 155-69.
42. McLean PG, Aston D, Sarkar D, Ahluwalia A. Protease-activated receptor-2 activation causes EDHF-like coronary vasodilation: selective preservation in ischemia/reperfusion injury: involvement of lipoxygenase products, VR1 receptors, and C-fibers. Circ Res 2002; 90: 465-72.
43. Hamilton JR, Cocks TM. Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery. Br J Pharmacol 2000; 130: 181-8.
44. McGuire JJ, Gui Y, Wang X, Loutzenhiser RD, Triggle CR, Hollenberg MD. In: Vanhoutte PM, Ed. EDHF 2002. London, Taylor & Francis 2003; 47-54.
45. Compton SJ, McGuire JJ, Saifeddine M, Hollenberg MD. Restricted ability of human mast cell tryptase to activate proteinase-activated receptor-2 in rat aorta. Can J Physiol Pharmacol 2002; 80: 987-92.
46. Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 1998; 396: 269-72.
47. Edwards G, Weston AH. Potassium and potassium clouds in endothelium-dependent hyperpolarizations. Pharmacol Res 2004; 49: 535-41.
48. Shimokawa H, Matoba T. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pharmacol Res 2004; 49: 543-9.
49. Fleming I. Cytochrome P450 epoxygenases as EDHF synthase(s). Pharmacol Res 2004; 49: 525-33.
50. Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23: 374-80.
51. Griffith TM, Endothelium-dependent smooth muscle hyperpolarization: do gap junctions provide a unifying hypothesis? Br J Pharmacol 2004; 141: 881-903.
52. Griffith TM, Chaytor AT, Edwards DH. The obligatory link: role of gap junctional communication in endothelium-dependent smooth muscle hyperpolarization. Pharmacol Res 2004; 49: 551-64.
53. McGuire JJ, Ding H, Triggle CR. Endothelium-derived relaxing factors: a focus on endothelium-derived hyperpolarizing factor(s). Can J Physiol Pharmacol 2001; 79: 443-70.
54. Sobey CG, Moffatt JD, Cocks TM. Evidence for selective effects of chronic hypertension on cerebral artery vasodilatation to protease-activated receptor-2 activation. Stroke 1999; 30: 1933-40.
55. Shpacovitch VM, Brzoska T, Buddenkotte J, Stroh C, Sommerhoff CP, Ansel JC, et al. Agonists of proteinase-activated receptor 2 induce cytokine release and activation of nuclear transcription factor kappaB in human dermal microvascular endothelial cells. J Invest Dermatol 2002; 118: 380-5.
56. Ogata H, Hibi T. Cytokine and anti-cytokine therapies for inflammatory bowel disease. Curr Pharm Des 2003; 9: 1107-13.
57. Taylor PC. Anti-cytokines and cytokines in the treatment of rheumatoid arthritis. Curr Pharm Des 2003; 9: 1095-106.
58. Ito H. Anti-interleukin-6 therapy for Crohn's disease. Curr Pharm Des 2003; 9: 295-305.
59. Remick DG. Cytokine therapeutics for the treatment of sepsis: why has nothing worked? Curr Pharm Des 2003; 9: 75-82.
60. D'Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P, et al. Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. J Histochem Cytochem 1998; 46: 157-64.
61. D'Andrea MR, Rogahn CJ, Andrade-Gordon P. Localization of protease-activated receptors-1 and -2 in human mast cells: indications for an amplified mast cell degranulation cascade. Biotech Histochem 2000; 75: 85-90.
62. D'Andrea MR, Derian CK, Santulli RJ, Andrade-Gordon P. Differential expression of protease-activated receptors-1 and -2 in stromal fibroblasts of normal, benign, and malignant human tissues. Am J Pathol 2001; 158: 2031-41.
63. Nystedt S, Ramakrishnan V, Sundelin J. The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells. Comparison with the thrombin receptor. J Biol Chem 1996; 271: 14910-5.
64. Bono F, Lamarche I, Herbert JM. Induction of vascular smooth muscle cell growth by selective activation of the proteinase activated receptor-2 (PAR-2). Biochem Biophys Res Commun 1997; 241: 762-4.
65. Cicala C, Pinto A, Bucci M, Sorrentino R, Walker B, Harriot P, et al. Protease-activated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo. Circulation 1999; 99: 2590-7.
66. Papadaki M, Ruef J, Nguyen KT, Li F, Patterson C, Eskin SG, et al. Differential regulation of protease activated receptor-1 and tissue plasminogen activator expression by shear stress in vascular smooth muscle cells. Circ Res 1998; 83: 1027-34.
67. Cicala C, Pinto A, Bucci M, Sorrentino R, Walker B, Harriot P, et al. Protease-activated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo. Circulation 1999; 99: 2590-7.
68. Damiano BP, D'Andrea MR, de Garavilla L, Cheung WM, Andrade-Gordon P. Increased expression of protease activated receptor-2 (PAR-2) in balloon-injured rat carotid artery. Thromb Haemost 1999; 81: 808-14.
69. Damiano BP, D'Andrea MR, de Garavilla L, Cheung WM, Andrade-Gordon P. Increased expression of protease activated receptor-2 (PAR-2) in balloon-injured rat carotid artery. Thromb Haemost 1999; 81: 808-14.
70. Koshikawa N, Nagashima Y, Miyagi Y, Mizushima. H, Yanoma S, Yasumitsu H, et al. Expression of trypsin in vascular endothelial cells. FEBS Lett 1997; 409: 442-8.
71. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995; 92: 1084-8.
72. Pannirselvam M, Anderson T, Triggle CR. Endothelial cell dysfunction in Type I and II diabetes: The cellular basis for dysfunction. Drug Development Research 2003; 58:28-41.
73. Riewald M, Ruf W. Orchestration of coagulation protease signaling by tissue factor. Trends Cardiovasc Med 2002; 12: 149-54.
74. Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci USA 2000; 97: 5255-60.
75. Waldron GJ, Ding H, Lovren F, Kubes P, Triggle CR. Acetylcholine-induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase. Br J Pharmacol 1999; 128: 653-8.
76. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377: 239-42.
77. Cocks TM, Moffatt JD. Protease-activated receptors: sentries for inflammation? Trends Pharmacol Sci 2000; 21: 103-8.
78. Selemidis S, Cocks TM. Endothelium-dependent hyperpolarization as a remote anti-atherogenic mechanism. Trends Pharmacol Sci 2002; 23: 213-20.
79. Feletou M, Vanhoutte PM. EDHF: new therapeutic targets? Pharmacol Res 2004; 49: 565-80.
80. Kurowska EM. Nitric oxide therapies in vascular diseases. Curr Pharm Des 2002; 8: 155-66.
81. Compton SJ, Cairns JA, Palmer KJ, Al Ani B, Hollenberg MD, Walls AF. A polymorphic protease-activated receptor 2 (PAR2) displaying reduced sensitivity to trypsin and differential responses to PAR agonists. J Biol Chem 2000; 275: 39207-12.
82. Nystedt S, Emilsson K, Larsson AK, Strombeck B, Sundelin J. Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2. Eur J Biochem 1995; 232: 84-9.
83. Jin E, Fujiwara M, Pan X, Ghazizadeh M, Arai S, Ohaki Y, et al. Protease-activated receptor (PAR)-1 and PAR-2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas. Cancer 2003; 97: 703-13.
84. Kennedy AR. Chemopreventive agents: protease inhibitors. Pharmacol Ther 1998; 78: 167-209.
85. Meyskens FL. Development of Bowman-Birk inhibitor for chemoprevention of oral head and neck cancer. Ann N Y Acad Sci 2001; 952: 116-23.
86. Ahn HS, Chackalamannil S, Boykow G, Graziano MP, Foster C. Development of proteinase-activated receptor 1 antagonists as therapeutic agents for thrombosis, restenosis and inflammatory diseases. Curr Pharm Design 2003; 9(28): 2349-65.
87. Ishikawa K. Heme oxygenase-1 against vascular insufficiency: roles of atherosclerotic disorders. Curr Pharm Design 2003; 9(30): 2489-97.
88. Kurowska EM. Nitric oxide therapies in vascular diseases. Curr Pharm Design 2002; 8(3): 155-66.