Selective thromboxane inhibition after vascular protectant AGI-1067: results of assessment of lipoprotein profiles (ALPS) biomarkers in vitro and in vivo substudy
Tóm tắt
Background Oxidative stress play an important role triggering platelet/endothelial activation. AGI-1067 is a novel, phenolic antioxidant, and vascular protectant which dose-dependently inhibits PEA biomarkers in vitro. Whether treatment with AGI-1067 alters platelets in vivo is not known. We serially assessed release of established PEA biomarkers in subjects treated with AGI-1067 versus placebo in the frame of Assessment of Lipoprotein Profiles Randomized Trial (ALPS). Methods Healthy subjects (18–65 years) with multiple risk factors for coronary artery disease were randomized 1:1 to receive 300 mg AGI-1067 (n = 112) or matching placebo (n = 117) daily for 12 weeks. Anticoagulants, aspirin, NSAIDS, and COX inhibitors were not permitted in this study. Plasma samples were collected at baseline, and at week 12 after randomization. Platelet factor 4 (PF4), β-thromboglobulin (βTG), P-selectin, thromboxane (TxB2), and prostacyclin (6-keto-PGF1a) were measured by ELISA. Results Treatment with AGI-1067 was associated with a highly significant reduction of TxB2 release (P < 0.0001) when compared to the placebo. There were no differences in PF4, βTG, P-selectin, and 6-keto-PGF1a between and within groups. AGI-1067 also inhibits TxB2 release from calcium ionophore (A23187)-stimulated human platelets with the IC50 equals 1 μM; but does not interfere with 6-keto-PGF1α release in either A23187-, or TXA2-stimulated human aortic endothelial cells. Conclusion AGI-1067 selectively reduces TxB2 production from stimulated platelets, and diminishes plasma TxB2 levels in ALPS participants. These data support earlier in vitro, and pilot ex vivo experiments suggesting antiplatelet properties of AGI-1067. Lack of 6-keto-PGF1a down regulation may represent an attractive advantage of AGI-1067 over currently available antiplatelet regimens.
Tài liệu tham khảo
Libby P (2003) Vascular biology of atherosclerosis: overview and state of the art. Am J Cardiol 91(suppl):3A–6A
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320:915–924
Marui N, Offermann MK, Swerlick R et al (1993) Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant sensitive mechanism in human vascular endothelial cells. J Clin Invest 92:1866–1874
Satriano JA, Shuldiner M, Hora K, Xing Y, Shan Z, Schlondorff D (1993) Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1 and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobuolin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. J Clin Invest 92:1564–1571
Ali MH, Schlidt SA, Chandel NS, Hynes KL, Schumacker PT, Gewertz BL (1999) Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction. Am J Physiol 277(5 Pt 1):L1057–L1065
Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H (2003) Role of oxidative stress in atherosclerosis. Am J Cardiol 91(suppl):7A–11A
Rodes J, Cote G, Lesperance J, Bourassa MG, Doucet S, Bilodeau L, Bertrand OF, Harel F, Gallo R, Tardif JC (1998) Prevention of restenosis after angioplasty in small coronary arteries with probucol. Circulation 97:429–436
Cote G, Tardif JC, Lesperance J, Lambert J, Bourassa M, Bonan R, Gosselin G, Joyal M, Tanguay JF, Nattel S, Gallo R, Crepeau J (1999) Effects of probucol on vascular remodeling after coronary angioplasty. Multivitamins and Protocol Study Group. Circulation 99:30–35
Wasserman MA, Sundell CL, Kunsch C, Edwards D, Meng CQ, Medford RM (2003) Chemistry and pharmacology of vascular protectants: a novel approach to the treatment of atherosclerosis and coronary artery disease. Am J Cardiol 91(3A):34A–40A
Narizhneva NV, Razorenova OV, Podrez EA, Chen J, Chandrasekharan UM, Dicorleto PE, Plow EF, Topol EJ, Byzova TV (2005) Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium. FASEB J 19:1158–1160
van der Zijpp YJ, Poot AA, Feijen J (2003) ICAM-1 and VCAM-1 expression by endothelial cells grown on fibronectin-coated TCPS and PS. J Biomed Mater Res A 65:51–59
Gawaz M, Page S, Massberg S et al (2002) Transient platelet interaction induces MCP-1 production by endothelial cells via I kappa B kinase complex activation. Thromb Haemost 88:307–314
Mayer K, Merfels M, Muhly-Reinholz M et al (2002) Omega-3 fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial PAF generation. Am J Physiol Heart Circ Physiol 283:H811–H818
Serebruany V, Malinin A, Scott R (2006) The in vitro effects of a novel vascular protectant, AGI-1067, on platelet aggregation and major receptor expression in subjects with multiple risk factors for vascular disease. J Cardiovasc Pharmacol Ther 11:191–196
National Cholesterol Education Program National Heart, Lung, and Blood Institute National Institutes of Health. NIH Publication No. 01-3670, May (2001)
Morgan CC (2003) Sample size re-estimation in group-sequential response-adaptive clinical trials. Stat Med 22:3843–3857
Tardif JC, Côté G, Lespérance J et al (1997) Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med 337:365–372
Rodés J, Tardif JC, Lespérance J et al (1998) Prevention of restenosis after angioplasty in small coronary arteries with probucol. Circulation 97:429–436
Tardif JC, Côté G, Lespérance J et al (2001) Impact of residual plaque burden after balloon angioplasty in the MultiVitamins and Probucol (MVP) trial. Can J Cardiol 17:49–55
Yokoi H, Daida H, Kuwabara Y et al (1997) Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: the Probucol Angioplasty Restenosis Trial. J Am Coll Cardiol 30:855–862
Watanabe K, Sekyia M, Ikeda S et al (1996) Preventive effects of probucol on restenosis after percutaneous transluminal coronary angioplasty. Am Heart J 132:23–29
Lee YJ, Daida H, Yokoi H et al (1996) Effectiveness of probucol in preventing restenosis after percutaneous transluminal coronary angioplasty. Jpn Heart J 37:327–332
Tardif JC, Gregoire J, Schwartz L et al (2003) Effects of AGI-1067 and probucol after percutaneous coronary interventions. Circulation 107:552–558
Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143
Kunsch C, Luchoomun J, Grey JY et al (2004) Selective inhibition of endothelial and monocyte redox-sensitive genes by AGI-1067: a novel antioxidant and anti-inflammatory agent. J Pharmacol Exp Ther 308:820–829
Li H, Cybulsky MI, Gimbrone MA Jr, Libby P (1993) An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb 13:197–204
Iiyama K, Hajra L, Iiyama M, Li H, DiChiara M, Medoff BD, Cybulsky MI (1999) Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res 85:199–207
Satriano JA, Shuldiner M, Hora K, Xing Y, Shan Z, Schlondorff D (1993) Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1 and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobuolin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase. J Clin Invest 92:1564–1571
O’Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD (1993) Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques: implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest 92:945–951
Gerszten RE, Lim Y, Ding HT, Snapp K, Kansas G, Dichek DA, Cabanas C, Sanchez-Madrid F, Gimbrone MA Jr, Rosenzweig A, Luscinskas FW (1998) Adhesion of monocytes to vascular cell adhesion molecule-1-transduced human endothelial cells: implications for atherogenesis. Circ Res 82:871–878
Rohde LE, Lee RT, Rivero J, Jamacochian M, Arroyo LH, Briggs W, Rifai N, Libby P, Creager MA, Ridker PM (1998) Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 18:1765–1770
Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J (2001) Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 104:1336–1342
Hamberg M, Svensson J, Samuelsson B (1975) Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci USA 72:2994
Needleman P, Minkes M, Raz A (1976) Thromboxanes: selective biosynthesis and distinct biological properties. Science 193:163–165
Higgs GA, Monsada S, Salmon JA, Seager K (1983) The source of thromboxane and prostaglandins in experimental inflammation. Br J Pharmacol 79:863–868
Ruggeri ZM (1997) von Willerbrand factor. J Clin Invest 99:559–564
Ogletree ML (1987) Overview of physiological and pathophysiological effects of thromboxane A2. Fed Proc 46:133–138
Lefer AM, H Darius (1987) A pharmacological approach to thromboxane receptor antagonism. Fed Proc 46:144–814
Zucker MB (1980) The functioning of blood platelets. Sci Am 242:86–103
Raychowdhury MK, Yukawa M, Collins LJ, McGrail SH, Kent KC, Ware JA (1994) Alternative splicing produces a divergent cytoplasmic tail in the human endothelial thromboxane A2 receptor. J Biol Chem 269:19256–19261
Ishizuka T, Kawakami M, Hidaka T, Matsuki Y, Takamizawa M, Suzuki K, Kurita A, Nakamura H (1998) Stimulation with thromboxane A2 (TXA2) receptor agonist enhances ICAM-1, VCAM-1 or ELAM-1 expression by human vascular endothelial cells. Clin Exp Immunol 112:464–470
Mitsuhashi M, Tanaka A, Fujisawa C, Kawamoto K, Itakura A, Takaku M, Hironaka T, Sawada S, Matsuda H (2001) Necessity of thromboxane A2 for initiation of platelet-mediated contact sensitivity: dual activation of platelets and vascular endothelial cells. J Immunol 166:617–623
Gurbel PA, Kereiakes DJ, Dalesandro MR, Bahr RD, O’Connor CM, Serebruany VL (2000) The role of soluble and platelet-bound P-selectin in discriminating cardiac from non-cardiac chest pain at presentation in the emergency department. Am Heart J 139:320–328