Platelet Oxidative Stress and its Relationship with Cardiovascular Diseases in Type 2 Diabetes Mellitus Patients

Mohammed        El Haouari
Abstract

Enhanced platelet activation and thrombosis are linked to various cardiovascular diseases (CVD). Among other mechanisms, oxidative stress seems to play a pivotal role in platelet hyperactivity. Indeed, upon stimulation by physiological agonists, human platelets generate and release several types of reactive oxygen species (ROS) such as O2 -, H2O2 or OH-, further amplifying the platelet activation response via various signalling pathways, including, formation of isoprostanes, Ca2+ mobilization and NO inactivation. Furthermore, excessive platelet ROS generation, incorporation of free radicals from environment and/or depletion of antioxidants induce pro-oxidant, pro-inflammatory and platelet hyperaggregability effects, leading to the incidence of cardiovascular events. Here, we review the current knowledge regarding the effect of oxidative stress on platelet signaling pathways and its implication in CVD such as type 2 diabetes mellitus. We also summarize the role of natural antioxidants included in vegetables, fruits and medicinal herbs in reducing platelet function via an oxidative stress-mediated mechanism.
Keywords: Platelets, reactive oxygen species, cardiovascular diseases, diabetes mellitus, antioxidants, signal transduction.
[1] 
Begonja, A.J. NO/cGMP and ROS pathways in regulation
of platelet function and megakaryocyte maturation, Dissertation;
Julius-Maximilians University: Wurzburg. 2007.
[2] 
Keaney, J.F. Jr.; Larson, M.G.; Vasan, R.S.; Wilson, P.W.; Lipinska, I.; Corey, D.; Massaro, J.M.; Sutherland, P.; Vita, J.A.; Benjamin, E.J.; Framingham, S. Framingham Study. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler. Thromb. Vasc. Biol.,  2003, 23(3), 434-439.
[http://dx.doi.org/10.1161/01.ATV.0000058402.34138.11] [PMID:  12615693] 
[3] 
Alexandru, N.; Popov, D.; Georgescu, A. Platelet dysfunction in vascular pathologies and how can it be treated. Thromb. Res.,  2012, 129(2), 116-126.
[http://dx.doi.org/10.1016/j.thromres.2011.09.026] [PMID:  22035630] 
[4] 
Tsoumani, M.E.; Kalantzi, K.I.; Goudevenos, I.A.; Tselepis, A.D. Platelet-mediated inflammation in cardiovascular disease. Potential role of platelet-endothelium interactions. Curr. Vasc. Pharmacol.,  2012, 10(5), 539-549.
[http://dx.doi.org/10.2174/157016112801784602] [PMID:  22338568] 
[5] 
Willoughby, S.; Holmes, A.; Loscalzo, J. Platelets and cardiovascular disease. Eur. J. Cardiovasc. Nurs.,  2002, 1(4), 273-288.
[http://dx.doi.org/10.1016/S1474-51510200038-5] [PMID:  14622657] 
[6] 
Pignatelli, P.; Pulcinelli, F.M.; Lenti, L.; Gazzaniga, P.P.; Violi, F. Hydrogen peroxide is involved in collagen-induced platelet activation. Blood,  1998, 91(2), 484-490.
[PMID:  9427701] 
[7] 
Rosado, J.A.; González, A.; Salido, G.M.; Pariente, J.A. Effects of reactive oxygen species on actin filament polymerisation and amylase secretion in mouse pancreatic acinar cells. Cell. Signal.,  2002, 14(6), 547-556.
[http://dx.doi.org/10.1016/S0898-6568(01)00273-X] [PMID:  11897495] 
[8] 
Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev.,  2002, 82(1), 47-95.
[http://dx.doi.org/10.1152/physrev.00018.2001] [PMID:  11773609] 
[9] 
Marcus, A.J.; Silk, S.T.; Safier, L.B.; Ullman, H.L. Superoxide production and reducing activity in human platelets. J. Clin. Invest.,  1977, 59(1), 149-158.
[http://dx.doi.org/10.1172/JCI108613] [PMID:  187622] 
[10] 
Violi, F.; Pignatelli, P. Platelet oxidative stress and thrombosis. Thromb. Res.,  2012, 129(3), 378-381.
[http://dx.doi.org/10.1016/j.thromres.2011.12.002] [PMID:  22209450] 
[11] 
Wachowicz, B.; Olas, B.; Zbikowska, H.M.; Buczyński, A. Generation of reactive oxygen species in blood platelets. Platelets,  2002, 13(3), 175-182.
[http://dx.doi.org/10.1080/09533710022149395] [PMID:  12180500] 
[12] 
Dixon, L.J.; Hughes, S.M.; Rooney, K.; Madden, A.; Devine, A.; Leahey, W.; Henry, W.; Johnston, G.D.; McVeigh, G.E. Increased superoxide production in hypertensive patients with diabetes mellitus: role of nitric oxide synthase. Am. J. Hypertens.,  2005, 18(6), 839-843.
[http://dx.doi.org/10.1016/j.amjhyper.2005.01.004] [PMID:  15925745] 
[13] 
Seno, T.; Inoue, N.; Gao, D.; Okuda, M.; Sumi, Y.; Matsui, K.; Yamada, S.; Hirata, K.I.; Kawashima, S.; Tawa, R.; Imajoh-Ohmi, S.; Sakurai, H.; Yokoyama, M. Involvement of NADH/NADPH oxidase in human platelet ROS production. Thromb. Res.,  2001, 103(5), 399-409.
[http://dx.doi.org/10.1016/S0049-3848(01)00341-3] [PMID:  11553372] 
[14] 
Iuliano, L.; Colavita, A.R.; Leo, R.; Praticò, D.; Violi, F. Oxygen free radicals and platelet activation. Free Radic. Biol. Med.,  1997, 22(6), 999-1006.
[http://dx.doi.org/10.1016/S0891-5849(96)00488-1] [PMID:  9034239] 
[15] 
Stokes, K.Y.; Russell, J.M.; Jennings, M.H.; Alexander, J.S.; Granger, D.N.; Platelet-associated, N.A.D. Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia. Free Radic. Biol. Med.,  2007, 43(1), 22-30.
[http://dx.doi.org/10.1016/j.freeradbiomed.2007.02.027] [PMID:  17561090] 
[16] 
El Haouari, M.J.I.; Mekhfi, H.; Rosado, J.A.; Salido, G.M. Urtica dioica extract reduces platelet hyperaggregability in type 2 diabetes mellitus by inhibition of oxidant production, Ca2+ mobilization and protein tyrosine phosphorylation. J. Appl. Biomed.,  2007, 5, 105-113.
[http://dx.doi.org/10.32725/jab.2007.015] 
[17] 
Cesbron, J.Y.; Capron, A.; Vargaftig, B.B.; Lagarde, M.; Pincemail, J.; Braquet, P.; Taelman, H.; Joseph, M. Platelets mediate the action of diethylcarbamazine on microfilariae. Nature,  1987, 325(6104), 533-536.
[http://dx.doi.org/10.1038/325533a0] [PMID:  3808054] 
[18] 
Jiang, F.; Zhang, Y.; Dusting, G.J. NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol. Rev.,  2011, 63(1), 218-242.
[http://dx.doi.org/10.1124/pr.110.002980] [PMID:  21228261] 
[19] 
Begonja, A.J.; Teichmann, L.; Geiger, J.; Gambaryan, S.; Walter, U. Platelet regulation by NO/cGMP signaling and NAD(P)H oxidase-generated ROS. Blood Cells Mol. Dis.,  2006, 36(2), 166-170.
[http://dx.doi.org/10.1016/j.bcmd.2005.12.028] [PMID:  16469512] 
[20] 
Winocour, P.D.; Watala, C.; Kinglough-Rathbone, R.L. Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ratio in isolated platelet membranes from diabetic and control subjects. Thromb. Haemost.,  1992, 67(5), 567-571.
[http://dx.doi.org/10.1055/s-0038-1648495] [PMID:  1519216] 
[21] 
El Haouari, M.; Rosado, J.A. Platelet signalling abnormalities in patients with type 2 diabetes mellitus: a review. Blood Cells Mol. Dis.,  2008, 41(1), 119-123.
[http://dx.doi.org/10.1016/j.bcmd.2008.02.010] [PMID:  18387322] 
[22] 
Li, J.M.; Shah, A.M. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am. J. Physiol. Regul. Integr. Comp. Physiol.,  2004, 287(5), R1014-R1030.
[http://dx.doi.org/10.1152/ajpregu.00124.2004] [PMID:  15475499] 
[23] 
Del Principe, D.; Menichelli, A.; De Matteis, W.; Di Giulio, S.; Giordani, M.; Savini, I.; Agro, A.F. Hydrogen peroxide is an intermediate in the platelet activation cascade triggered by collagen, but not by thrombin. Thromb. Res.,  1991, 62(5), 365-375.
[http://dx.doi.org/10.1016/0049-3848(91)90010-T] [PMID:  1896957] 
[24] 
Dayal, S.; Wilson, K.M.; Motto, D.G.; Miller, F.J. Jr.; Chauhan, A.K.; Lentz, S.R. Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis. Circulation,  2013, 127(12), 1308-1316.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.000966] [PMID:  23426106] 
[25] 
Berndt, M.C.; Phillips, D.R. Interaction of thrombin with platelets: purification of the thrombin substrate. Ann. N. Y. Acad. Sci.,  1981, 370, 87-95.
[http://dx.doi.org/10.1111/j.1749-6632.1981.tb29724.x] [PMID:  6943980] 
[26] 
Chlopicki, S.; Olszanecki, R.; Janiszewski, M.; Laurindo, F.R.; Panz, T.; Miedzobrodzki, J. Functional role of NADPH oxidase in activation of platelets. Antioxid. Redox Signal.,  2004, 6(4), 691-698.
[http://dx.doi.org/10.1089/1523086041361640] [PMID:  15242549] 
[27] 
Krötz, F.; Sohn, H.Y.; Gloe, T.; Zahler, S.; Riexinger, T.; Schiele, T.M.; Becker, B.F.; Theisen, K.; Klauss, V.; Pohl, U. NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment. Blood,  2002, 100(3), 917-924.
[http://dx.doi.org/10.1182/blood.V100.3.917] [PMID:  12130503] 
[28] 
Fauvel, F.; Legrand, Y.J.; Caen, J.P. Platelet adhesion to type I collagen and alpha 1 (I)3 trimers: involvement of the C-terminal alpha 1 (I) CB6A peptide. Thromb. Res.,  1978, 12(2), 273-285.
[http://dx.doi.org/10.1016/0049-3848(78)90298-0] [PMID:  635843] 
[29] 
Balleisen, L.; Marx, R.; Kühn, K. Platelet-collagen interaction. The influence of native and modified collagen (Type I) on the aggregation of human platelets. Haemostasis,  1976, 5(3), 155-164.
[PMID:  1002002] 
[30] 
Clutton, P.; Miermont, A.; Freedman, J.E. Regulation of endogenous reactive oxygen species in platelets can reverse aggregation. Arterioscler. Thromb. Vasc. Biol.,  2004, 24(1), 187-192.
[http://dx.doi.org/10.1161/01.ATV.0000105889.29687.CC] [PMID:  14604832] 
[31] 
Caccese, D.; Praticò, D.; Ghiselli, A.; Natoli, S.; Pignatelli, P.; Sanguigni, V.; Iuliano, L.; Violi, F. Superoxide anion and hydroxyl radical release by collagen-induced platelet aggregation--role of arachidonic acid metabolism. Thromb. Haemost.,  2000, 83(3), 485-490.
[http://dx.doi.org/10.1055/s-0037-1613841] [PMID:  10744158] 
[32] 
Begonja, A.J.; Gambaryan, S.; Geiger, J.; Aktas, B.; Pozgajova, M.; Nieswandt, B.; Walter, U.; Platelet, N.A.D. Platelet NAD(P)H-oxidase-generated ROS production regulates alphaIIbbeta3-integrin activation independent of the NO/cGMP pathway. Blood,  2005, 106(8), 2757-2760.
[http://dx.doi.org/10.1182/blood-2005-03-1047] [PMID:  15976180] 
[33] 
Soulet, C.; Gendreau, S.; Missy, K.; Benard, V.; Plantavid, M.; Payrastre, B. Characterisation of Rac activation in thrombin- and collagen-stimulated human blood platelets. FEBS Lett.,  2001, 507(3), 253-258.
[http://dx.doi.org/10.1016/S0014-5793(01)02984-2] [PMID:  11696351] 
[34] 
Lassègue, B.; Griendling, K.K. NADPH oxidases: functions and pathologies in the vasculature. Arterioscler. Thromb. Vasc. Biol.,  2010, 30(4), 653-661.
[http://dx.doi.org/10.1161/ATVBAHA.108.181610] [PMID:  19910640] 
[35] 
Salvemini, D.; Radziszewski, W.; Mollace, V.; Moore, A.; Willoughby, D.; Vane, J. Diphenylene iodonium, an inhibitor of free radical formation, inhibits platelet aggregation. Eur. J. Pharmacol.,  1991, 199(1), 15-18.
[http://dx.doi.org/10.1016/0014-2999(91)90631-Y] [PMID:  1716574] 
[36] 
Pignatelli, P.; Carnevale, R.; Di Santo, S.; Bartimoccia, S.; Sanguigni, V.; Lenti, L.; Finocchi, A.; Mendolicchio, L.; Soresina, A.R.; Plebani, A.; Violi, F. Inherited human gp91phox deficiency is associated with impaired isoprostane formation and platelet dysfunction. Arterioscler. Thromb. Vasc. Biol.,  2011, 31(2), 423-434.
[http://dx.doi.org/10.1161/ATVBAHA.110.217885] [PMID:  21071703] 
[37] 
Delaney, M.K.; Kim, K.; Estevez, B.; Xu, Z.; Stojanovic-Terpo, A.; Shen, B.; Ushio-Fukai, M.; Cho, J.; Du, X. Differential roles of the NADPH-oxidase 1 and 2 in platelet activation and thrombosis. Arterioscler. Thromb. Vasc. Biol.,  2016, 36(5), 846-854.
[http://dx.doi.org/10.1161/ATVBAHA.116.307308] [PMID:  26988594] 
[38] 
Walsh, T.G.; Berndt, M.C.; Carrim, N.; Cowman, J.; Kenny, D.; Metharom, P. The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation. Redox Biol.,  2014, 2, 178-186.
[http://dx.doi.org/10.1016/j.redox.2013.12.023] [PMID:  24494191] 
[39] 
Cardoso, A.R.; Chausse, B.; da Cunha, F.M.; Luévano-Martínez, L.A.; Marazzi, T.B.; Pessoa, P.S.; Queliconi, B.B.; Kowaltowski, A.J. Mitochondrial compartmentalization of redox processes. Free Radic. Biol. Med.,  2012, 52(11-12), 2201-2208.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.03.008] [PMID:  22564526] 
[40] 
Leo, R.; Praticò, D.; Iuliano, L.; Pulcinelli, F.M.; Ghiselli, A.; Pignatelli, P.; Colavita, A.R.; FitzGerald, G.A.; Violi, F. Platelet activation by superoxide anion and hydroxyl radicals intrinsically generated by platelets that had undergone anoxia and then reoxygenated. Circulation,  1997, 95(4), 885-891.
[http://dx.doi.org/10.1161/01.CIR.95.4.885] [PMID:  9054746] 
[41] 
Iuliano, L.; Pedersen, J.Z.; Praticò, D.; Rotilio, G.; Violi, F. Role of hydroxyl radicals in the activation of human platelets. Eur. J. Biochem.,  1994, 221(2), 695-704.
[http://dx.doi.org/10.1111/j.1432-1033.1994.tb18782.x] [PMID:  8174549] 
[42] 
Del Principe, D.; Menichelli, A.; De Matteis, W.; Di Corpo, M.L.; Di Giulio, S.; Finazzi-Agro, A. Hydrogen peroxide has a role in the aggregation of human platelets. FEBS Lett.,  1985, 185(1), 142-146.
[http://dx.doi.org/10.1016/0014-5793(85)80758-4] [PMID:  3996592] 
[43] 
Mehta, J.L.; Chen, L.Y.; Kone, B.C.; Mehta, P.; Turner, P. Identification of constitutive and inducible forms of nitric oxide synthase in human platelets. J. Lab. Clin. Med.,  1995, 125(3), 370-377.
[PMID:  7534807] 
[44] 
Olas, B.; Nowak, P.; Kolodziejczyk, J.; Wachowicz, B. The effects of antioxidants on peroxynitrite-induced changes in platelet proteins. Thromb. Res.,  2004, 113(6), 399-406.
[http://dx.doi.org/10.1016/j.thromres.2004.04.002] [PMID:  15226095] 
[45] 
Olas, B.; Wachowicz, B. Role of reactive nitrogen species in blood platelet functions. Platelets,  2007, 18(8), 555-565.
[http://dx.doi.org/10.1080/09537100701504087] [PMID:  17852770] 
[46] 
El Haouari, M.; Rosado, J.A. Platelet function in hypertension. Blood Cells Mol. Dis.,  2009, 42(1), 38-43.
[http://dx.doi.org/10.1016/j.bcmd.2008.07.003] [PMID:  18829351] 
[47] 
Elwood, P.C.; Beswick, A.D.; Sharp, D.S.; Yarnell, J.W.; Rogers, S.; Renaud, S. Whole blood impedance platelet aggregometry and ischemic heart disease. The caerphilly collaborative heart disease study. Arteriosclerosis,  1990, 10(6), 1032-1036.
[http://dx.doi.org/10.1161/01.ATV.10.6.1032] [PMID:  2244853] 
[48] 
Colwell, J.A.; Nesto, R.W. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care,  2003, 26(7), 2181-2188.
[http://dx.doi.org/10.2337/diacare.26.7.2181] [PMID:  12832332] 
[49] 
Bierman, E.L. George lyman duff memorial lecture. Atherogenesis in diabetes. Arterioscler. Thromb.,  1992, 12(6), 647-656.
[http://dx.doi.org/10.1161/01.ATV.12.6.647] [PMID:  1591228] 
[50] 
Grove, E.L.; Gregersen, S. Antiplatelet therapy in patients with diabetes mellitus. Curr. Vasc. Pharmacol.,  2012, 10(4), 494-505.
[http://dx.doi.org/10.2174/157016112800812818] [PMID:  22272895] 
[51] 
Chen, S.; Su, Y.; Wang, J. ROS-mediated platelet generation: a microenvironment-dependent manner for megakaryocyte proliferation, differentiation, and maturation. Cell Death Dis.,  2013, 4e, 722.
[http://dx.doi.org/10.1038/cddis.2013.253] [PMID:  23846224] 
[52] 
Awad, J.A.; Roberts, L.J., II; Burk, R.F.; Morrow, J.D. Isoprostanes--prostaglandin-like compounds formed in vivo independently of cyclooxygenase: use as clinical indicators of oxidant damage. Gastroenterol. Clin. North Am.,  1996, 25(2), 409-427.
[http://dx.doi.org/10.1016/S0889-8553(05)70255-7] [PMID:  9229581] 
[53] 
Praticó, D.; FitzGerald, G.A. Generation of 8-epiprostaglandin F2alpha by human monocytes. Discriminate production by reactive oxygen species and prostaglandin endoperoxide synthase-2. J. Biol. Chem.,  1996, 271(15), 8919-8924.
[http://dx.doi.org/10.1074/jbc.271.15.8919] [PMID:  8621535] 
[54] 
Delannoy, E.; Courtois, A.; Freund-Michel, V.; Leblais, V.; Marthan, R.; Muller, B. Hypoxia-induced hyperreactivity of pulmonary arteries: role of cyclooxygenase-2, isoprostanes, and thromboxane receptors. Cardiovasc. Res.,  2010, 85(3), 582-592.
[http://dx.doi.org/10.1093/cvr/cvp292] [PMID:  19710084] 
[55] 
Jourdan, K.B.; Evans, T.W.; Goldstraw, P.; Mitchell, J.A. Isoprostanes and PGE2 production in human isolated pulmonary artery smooth muscle cells: concomitant and differential release. FASEB J.,  1999, 13(9), 1025-1030.
[http://dx.doi.org/10.1096/fasebj.13.9.1025] [PMID:  10336884] 
[56] 
Redondo, P.C.; Ben-Amor, N.; Salido, G.M.; Bartegi, A.; Pariente, J.A.; Rosado, J.A. Ca2+-independent activation of Bruton’s tyrosine kinase is required for store-mediated Ca2+ entry in human platelets. Cell. Signal.,  2005, 17(8), 1011-1021.
[http://dx.doi.org/10.1016/j.cellsig.2004.11.019] [PMID:  15894173] 
[57] 
Abe, Ji.; Takahashi, M.; Ishida, M.; Lee, J.D.; Berk, B.C. c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1. J. Biol. Chem.,  1997, 272(33), 20389-20394.
[http://dx.doi.org/10.1074/jbc.272.33.20389] [PMID:  9252345] 
[58] 
Finkel, T. Oxygen radicals and signaling. Curr. Opin. Cell Biol.,  1998, 10(2), 248-253.
[http://dx.doi.org/10.1016/S0955-0674(98)80147-6] [PMID:  9561849] 
[59] 
Randriamboavonjy, V.; Pistrosch, F.; Bölck, B.; Schwinger, R.H.; Dixit, M.; Badenhoop, K.; Cohen, R.A.; Busse, R.; Fleming, I. Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone. Circulation,  2008, 117(1), 52-60.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.719807] [PMID:  18071073] 
[60] 
Nishigaki, I.; Hagihara, M.; Tsunekawa, H.; Maseki, M.; Yagi, K. Lipid peroxide levels of serum lipoprotein fractions of diabetic patients. Biochem. Med.,  1981, 25(3), 373-378.
[http://dx.doi.org/10.1016/0006-2944(81)90096-X] [PMID:  7271769] 
[61] 
Nourooz-Zadeh, J.; Tajaddini-Sarmadi, J.; McCarthy, S.; Betteridge, D.J.; Wolff, S.P. Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes,  1995, 44(9), 1054-1058.
[http://dx.doi.org/10.2337/diab.44.9.1054] [PMID:  7657028] 
[62] 
Gopaul, N.K.; Anggård, E.E.; Mallet, A.I.; Betteridge, D.J.; Wolff, S.P.; Nourooz-Zadeh, J. Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett.,  1995, 368(2), 225-229.
[http://dx.doi.org/10.1016/0014-5793(95)00649-T] [PMID:  7628610] 
[63] 
Davì, G.; Ciabattoni, G.; Consoli, A.; Mezzetti, A.; Falco, A.; Santarone, S.; Pennese, E.; Vitacolonna, E.; Bucciarelli, T.; Costantini, F.; Capani, F.; Patrono, C. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation,  1999, 99(2), 224-229.
[http://dx.doi.org/10.1161/01.CIR.99.2.224] [PMID:  9892587] 
[64] 
Davì, G.; Gresele, P.; Violi, F.; Basili, S.; Catalano, M.; Giammarresi, C.; Volpato, R.; Nenci, G.G.; Ciabattoni, G.; Patrono, C. Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation,  1997, 96(1), 69-75.
[http://dx.doi.org/10.1161/01.CIR.96.1.69] [PMID:  9236419] 
[65] 
Patrono, C.; Rocca, B. Type 2 diabetes, obesity, and aspirin responsiveness. J. Am. Coll. Cardiol.,  2017, 69(6), 613-615.
[http://dx.doi.org/10.1016/j.jacc.2016.11.049] [PMID:  28089179] 
[66] 
Csiszar, A.; Stef, G.; Pacher, P.; Ungvari, Z. Oxidative stress-induced isoprostane formation may contribute to aspirin resistance in platelets. Prostaglandins Leukot. Essent. Fatty Acids,  2002, 66(5-6), 557-558.
[http://dx.doi.org/10.1054/plef.2002.0399] [PMID:  12144879] 
[67] 
Iwase, E.; Tawata, M.; Aida, K.; Ozaki, Y.; Kume, S.; Satoh, K.; Qi, R.; Onaya, T. A cross-sectional evaluation of spontaneous platelet aggregation in relation to complications in patients with type II diabetes mellitus. Metabolism,  1998, 47(6), 699-705.
[http://dx.doi.org/10.1016/S0026-0495(98)90034-8] [PMID:  9627370] 
[68] 
Gabbianelli, R.; Falcioni, G.; Dow, C.S.; Vince, F.P.; Swoboda, B. A new method to evaluate spontaneous platelet aggregation in type 2 diabetes by Cellfacts. Clin. Chim. Acta,  2003, 329(1-2), 95-102.
[http://dx.doi.org/10.1016/S0009-8981(03)00012-3] [PMID:  12589971] 
[69] 
Sobol, A.B.; Watala, C. The role of platelets in diabetes-related vascular complications. Diabetes Res. Clin. Pract.,  2000, 50(1), 1-16.
[http://dx.doi.org/10.1016/S0168-8227(00)00160-1] [PMID:  10936664] 
[70] 
Cangemi, R.; Pignatelli, P.; Carnevale, R.; Nigro, C.; Proietti, M.; Angelico, F.; Lauro, D.; Basili, S.; Violi, F. Platelet isoprostane overproduction in diabetic patients treated with aspirin. Diabetes,  2012, 61(6), 1626-1632.
[http://dx.doi.org/10.2337/db11-1243] [PMID:  22427378] 
[71] 
Praticò, D.; Iuliano, L.; Ghiselli, A.; Alessandri, C.; Violi, F. Hydrogen peroxide as trigger of platelet aggregation. Haemostasis,  1991, 21(3), 169-174.
[PMID:  1773986] 
[72] 
Ben-Amor, N.; Redondo, P.C.; Bartegi, A.; Pariente, J.A.; Salido, G.M.; Rosado, J.A. A role for 5,6-epoxyeicosatrienoic acid in calcium entry by de novo conformational coupling in human platelets. J. Physiol.,  2006, 570(Pt 2), 309-323.
[http://dx.doi.org/10.1113/jphysiol.2005.100800] [PMID:  16308346] 
[73] 
Lopez, J.J.; Salido, G.M.; Gómez-Arteta, E.; Rosado, J.A.; Pariente, J.A. Thrombin induces apoptotic events through the generation of reactive oxygen species in human platelets. J. Thromb. Haemost.,  2007, 5(6), 1283-1291.
[http://dx.doi.org/10.1111/j.1538-7836.2007.02505.x] [PMID:  17567446] 
[74] 
Jardín, I.; Redondo, P.C.; Salido, G.M.; Pariente, J.A.; Rosado, J.A. Endogenously generated reactive oxygen species reduce PMCA activity in platelets from patients with non-insulin-dependent diabetes mellitus. Platelets,  2006, 17(5), 283-288.
[http://dx.doi.org/10.1080/09537100600745187] [PMID:  16928598] 
[75] 
Rosado, J.A.; Saavedra, F.R.; Redondo, P.C.; Hernández-Cruz, J.M.; Salido, G.M.; Pariente, J.A. Reduced plasma membrane Ca2+-ATPase function in platelets from patients with non-insulin-dependent diabetes mellitus. Haematologica,  2004, 89(9), 1142-1144.
[PMID:  15377479] 
[76] 
Saavedra, F.R.; Redondo, P.C.; Hernández-Cruz, J.M.; Salido, G.M.; Pariente, J.A.; Rosado, J.A. Store-operated Ca(2+) entry and tyrosine kinase pp60(src) hyperactivity are modulated by hyperglycemia in platelets from patients with non insulin-dependent diabetes mellitus. Arch. Biochem. Biophys.,  2004, 432(2), 261-268.
[http://dx.doi.org/10.1016/j.abb.2004.09.034] [PMID:  15542065] 
[77] 
Hangaishi, M.; Taguchi, J.; Miyata, T.; Ikari, Y.; Togo, M.; Hashimoto, Y.; Watanabe, T.; Kimura, S.; Kurokawa, K.; Ohno, M. Increased aggregation of human platelets produced by advanced glycation end products in vitro. Biochem. Biophys. Res. Commun.,  1998, 248(2), 285-292.
[http://dx.doi.org/10.1006/bbrc.1998.8945] [PMID:  9675128] 
[78] 
Creemers, E.E.; Tijsen, A.J.; Pinto, Y.M. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ. Res.,  2012, 110(3), 483-495.
[http://dx.doi.org/10.1161/CIRCRESAHA.111.247452] [PMID:  22302755] 
[79] 
Bronze-da-Rocha, E. MicroRNAs expression profiles in cardiovascular diseases. BioMed Res. Int.,  2014, 2014985408
[http://dx.doi.org/10.1155/2014/985408] [PMID:  25013816] 
[80] 
Ha, T.Y. MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw.,  2011, 11(3), 135-154.
[http://dx.doi.org/10.4110/in.2011.11.3.135] [PMID:  21860607] 
[81] 
Yang, Z.; Chen, H.; Si, H.; Li, X.; Ding, X.; Sheng, Q.; Chen, P.; Zhang, H. Serum miR-23a, a potential biomarker for diagnosis of pre-diabetes and type 2 diabetes. Acta Diabetol.,  2014, 51(5), 823-831.
[http://dx.doi.org/10.1007/s00592-014-0617-8] [PMID:  24981880] 
[82] 
Chen, X.; Ba, Y.; Ma, L.; Cai, X.; Yin, Y.; Wang, K.; Guo, J.; Zhang, Y.; Chen, J.; Guo, X.; Li, Q.; Li, X.; Wang, W.; Zhang, Y.; Wang, J.; Jiang, X.; Xiang, Y.; Xu, C.; Zheng, P.; Zhang, J.; Li, R.; Zhang, H.; Shang, X.; Gong, T.; Ning, G.; Wang, J.; Zen, K.; Zhang, J.; Zhang, C.Y. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res.,  2008, 18(10), 997-1006.
[http://dx.doi.org/10.1038/cr.2008.282] [PMID:  18766170] 
[83] 
Guay, C.; Roggli, E.; Nesca, V.; Jacovetti, C.; Regazzi, R. Diabetes mellitus, a microRNA-related disease? Transl. Res.,  2011, 157(4), 253-264.
[http://dx.doi.org/10.1016/j.trsl.2011.01.009] [PMID:  21420036] 
[84] 
Zampetaki, A.; Kiechl, S.; Drozdov, I.; Willeit, P.; Mayr, U.; Prokopi, M.; Mayr, A.; Weger, S.; Oberhollenzer, F.; Bonora, E.; Shah, A.; Willeit, J.; Mayr, M. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ. Res.,  2010, 107(6), 810-817.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.226357] [PMID:  20651284] 
[85] 
Landry, P.; Plante, I.; Ouellet, D.L.; Perron, M.P.; Rousseau, G.; Provost, P. Existence of a microRNA pathway in anucleate platelets. Nat. Struct. Mol. Biol.,  2009, 16(9), 961-966.
[http://dx.doi.org/10.1038/nsmb.1651] [PMID:  19668211] 
[86] 
Edelstein, L.C.; Bray, P.F. MicroRNAs in platelet production and activation. Blood,  2011, 117(20), 5289-5296.
[http://dx.doi.org/10.1182/blood-2011-01-292011] [PMID:  21364189] 
[87] 
Diehl, P.; Fricke, A.; Sander, L.; Stamm, J.; Bassler, N.; Htun, N.; Ziemann, M.; Helbing, T.; El-Osta, A.; Jowett, J.B.; Peter, K. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc. Res.,  2012, 93(4), 633-644.
[http://dx.doi.org/10.1093/cvr/cvs007] [PMID:  22258631] 
[88] 
Yuan, A.; Farber, E.L.; Rapoport, A.L.; Tejada, D.; Deniskin, R.; Akhmedov, N.B.; Farber, D.B. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One,  2009, 4(3)e4722
[http://dx.doi.org/10.1371/journal.pone.0004722] [PMID:  19266099] 
[89] 
Evans, D.J.; Jackman, L.E.; Chamberlain, J.; Crosdale, D.J.; Judge, H.M.; Jetha, K.; Norman, K.E.; Francis, S.E.; Storey, R.F. Platelet P2Y(12) receptor influences the vessel wall response to arterial injury and thrombosis. Circulation,  2009, 119(1), 116-122.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.762690] [PMID:  19103996] 
[90] 
Zhang, L.; Chopp, M.; Liu, X.; Teng, H.; Tang, T.; Kassis, H.; Zhang, Z.G. Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll-like receptor signaling pathway. Arterioscler. Thromb. Vasc. Biol.,  2012, 32(8), 1856-1864.
[http://dx.doi.org/10.1161/ATVBAHA.112.252619] [PMID:  22723435] 
[91] 
Hartwig, J.H. Mechanisms of actin rearrangements mediating platelet activation. J. Cell Biol.,  1992, 118(6), 1421-1442.
[http://dx.doi.org/10.1083/jcb.118.6.1421] [PMID:  1325975] 
[92] 
Perron, M.P.; Landry, P.; Plante, I.; Provost, P. Detection of human Dicer and Argonaute 2 catalytic activity. Methods Mol. Biol.,  2011, 725, 121-141.
[http://dx.doi.org/10.1007/978-1-61779-046-1_9] [PMID:  21528451] 
[93] 
Provost, P.; Dishart, D.; Doucet, J.; Frendewey, D.; Samuelsson, B.; Rådmark, O. Ribonuclease activity and RNA binding of recombinant human Dicer. EMBO J.,  2002, 21(21), 5864-5874.
[http://dx.doi.org/10.1093/emboj/cdf578] [PMID:  12411504] 
[94] 
Fleming, I.; Fisslthaler, B.; Dixit, M.; Busse, R. Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J. Cell Sci.,  2005, 118(Pt 18), 4103-4111.
[http://dx.doi.org/10.1242/jcs.02541] [PMID:  16118242] 
[95] 
Handin, R.I.; Karabin, R.; Boxer, G.J. Enhancement of platelet function by superoxide anion. J. Clin. Invest.,  1977, 59(5), 959-965.
[http://dx.doi.org/10.1172/JCI108718] [PMID:  192766] 
[96] 
Iuliano, L.; Praticò, D.; Ghiselli, A.; Bonavita, M.S.; Violi, F. Superoxide dismutase triggers activation of “primed” platelets. Arch. Biochem. Biophys.,  1991, 289(1), 180-183.
[http://dx.doi.org/10.1016/0003-9861(91)90458-U] [PMID:  1910314] 
[97] 
Wang, W.Q.; Zhang, H.F.; Gao, G.X.; Bai, Q.X.; Li, R.; Wang, X.M. Adiponectin inhibits hyperlipidemia-induced platelet aggregation via attenuating oxidative/nitrative stress. Physiol. Res.,  2011, 60(2), 347-354.
[PMID:  21114366] 
[98] 
Finkel, T. Redox-dependent signal transduction. FEBS Lett.,  2000, 476(1-2), 52-54.
[http://dx.doi.org/10.1016/S0014-5793(00)01669-0] [PMID:  10878249] 
[99] 
Ferroni, P.; Basili, S.; Falco, A.; Davì, G. Platelet activation in type 2 diabetes mellitus. J. Thromb. Haemost.,  2004, 2(8), 1282-1291.
[http://dx.doi.org/10.1111/j.1538-7836.2004.00836.x] [PMID:  15304032] 
[100] 
Morel, O.; Jesel, L.; Hugel, B.; Douchet, M.P.; Zupan, M.; Chauvin, M.; Freyssinet, J.M.; Toti, F. Protective effects of vitamin C on endothelium damage and platelet activation during myocardial infarction in patients with sustained generation of circulating microparticles. J. Thromb. Haemost.,  2003, 1(1), 171-177.
[http://dx.doi.org/10.1046/j.1538-7836.2003.00010.x] [PMID:  12871555] 
[101] 
Arthur, J.F.; Qiao, J.; Shen, Y.; Davis, A.K.; Dunne, E.; Berndt, M.C.; Gardiner, E.E.; Andrews, R.K. ITAM receptor-mediated generation of reactive oxygen species in human platelets occurs via Syk-dependent and Syk-independent pathways. J. Thromb. Haemost.,  2012, 10(6), 1133-1141.
[http://dx.doi.org/10.1111/j.1538-7836.2012.04734.x] [PMID:  22489915] 
[102] 
Shen, B.; Zhao, X.; O’Brien, K.A.; Stojanovic-Terpo, A.; Delaney, M.K.; Kim, K.; Cho, J.; Lam, S.C.; Du, X. A directional switch of integrin signalling and a new anti-thrombotic strategy. Nature,  2013, 503(7474), 131-135.
[http://dx.doi.org/10.1038/nature12613] [PMID:  24162846] 
[103] 
Pollock, J.D.; Williams, D.A.; Gifford, M.A.; Li, L.L.; Du, X.; Fisherman, J.; Orkin, S.H.; Doerschuk, C.M.; Dinauer, M.C. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat. Genet.,  1995, 9(2), 202-209.
[http://dx.doi.org/10.1038/ng0295-202] [PMID:  7719350] 
[104] 
Delaney, M.K.; Liu, J.; Zheng, Y.; Berndt, M.C.; Du, X. The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation. Arterioscler. Thromb. Vasc. Biol.,  2012, 32(11), 2761-2768.
[http://dx.doi.org/10.1161/ATVBAHA.112.254920] [PMID:  22995516] 
[105] 
Camilletti, A.; Moretti, N.; Giacchetti, G.; Faloia, E.; Martarelli, D.; Mantero, F.; Mazzanti, L. Decreased nitric oxide levels and increased calcium content in platelets of hypertensive patients. Am. J. Hypertens.,  2001, 14(4 Pt 1), 382-386.
[http://dx.doi.org/10.1016/S0895-7061(00)01297-8] [PMID:  11336186] 
[106] 
Alderton, W.K.; Cooper, C.E.; Knowles, R.G. Nitric oxide synthases: structure, function and inhibition. Biochem. J.,  2001, 357(Pt 3), 593-615.
[http://dx.doi.org/10.1042/bj3570593] [PMID:  11463332] 
[107] 
Naseem, K.M.; Riba, R. Unresolved roles of platelet nitric oxide synthase. J. Thromb. Haemost.,  2008, 6(1), 10-19.
[http://dx.doi.org/10.1111/j.1538-7836.2007.02802.x] [PMID:  17944990] 
[108] 
Loscalzo, J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ. Res.,  2001, 88(8), 756-762.
[http://dx.doi.org/10.1161/hh0801.089861] [PMID:  11325866] 
[109] 
De La Cruz, J.P.; Moreno, A.; Guerrero, A.; de La Cuesta, F.S. Antiplatelet effects of prostacyclin and nitric oxide in patients with type I diabetes and ischemic or edematous retinopathy. Platelets,  2001, 12(4), 210-217.
[http://dx.doi.org/10.1080/09537100120058748] [PMID:  11454255] 
[110] 
El-Omar, M.M.; Islam, N.; Broekman, M.J.; Drosopoulos, J.H.; Roa, D.C.; Lorin, J.D.; Sedlis, S.P.; Olson, K.E.; Pulte, E.D.; Marcus, A.J. The ratio of ADP- to ATP-ectonucleotidase activity is reduced in patients with coronary artery disease. Thromb. Res.,  2005, 116(3), 199-206.
[http://dx.doi.org/10.1016/j.thromres.2004.11.024] [PMID:  15935828] 
[111] 
Sase, K.; Michel, T. Expression of constitutive endothelial nitric oxide synthase in human blood platelets. Life Sci.,  1995, 57(22), 2049-2055.
[http://dx.doi.org/10.1016/0024-3205(95)02191-K] [PMID:  7475956] 
[112] 
Radomski, M.W.; Palmer, R.M.; Moncada, S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc. Natl. Acad. Sci. USA,  1990, 87(13), 5193-5197.
[http://dx.doi.org/10.1073/pnas.87.13.5193] [PMID:  1695013] 
[113] 
Randriamboavonjy, V.; Fleming, I. Endothelial nitric oxide synthase (eNOS) in platelets: how is it regulated and what is it doing there? Pharmacol. Rep.,  2005, 57(Suppl.), 59-65.
[114] 
Friebe, A.; Mergia, E.; Dangel, O.; Lange, A.; Koesling, D. Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase. Proc. Natl. Acad. Sci. USA,  2007, 104(18), 7699-7704.
[http://dx.doi.org/10.1073/pnas.0609778104] [PMID:  17452643] 
[115] 
Russo, I.; Doronzo, G.; Mattiello, L.; De Salve, A.; Trovati, M.; Anfossi, G. The activity of constitutive nitric oxide synthase is increased by the pathway cAMP/cAMP-activated protein kinase in human platelets. New insights into the antiaggregating effects of cAMP-elevating agents. Thromb. Res.,  2004, 114(4), 265-273.
[http://dx.doi.org/10.1016/j.thromres.2004.06.036] [PMID:  15381390] 
[116] 
Sudo, T.; Ito, H.; Kimura, Y. Phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) by the anti-platelet drug, cilostazol, in platelets. Platelets,  2003, 14(6), 381-390.
[http://dx.doi.org/10.1080/09537100310001598819] [PMID:  14602552] 
[117] 
Jensen, B.O.; Selheim, F.; Døskeland, S.O.; Gear, A.R.; Holmsen, H. Protein kinase A mediates inhibition of the thrombin-induced platelet shape change by nitric oxide. Blood,  2004, 104(9), 2775-2782.
[http://dx.doi.org/10.1182/blood-2004-03-1058] [PMID:  15265792] 
[118] 
Apostoli, G.L.; Solomon, A.; Smallwood, M.J.; Winyard, P.G.; Emerson, M. Role of inorganic nitrate and nitrite in driving nitric oxide-cGMP-mediated inhibition of platelet aggregation in vitro and in vivo. J. Thromb. Haemost.,  2014, 12(11), 1880-1889.
[http://dx.doi.org/10.1111/jth.12711] [PMID:  25163536] 
[119] 
Eigenthaler, M.; Nolte, C.; Halbrügge, M.; Walter, U. Concentration and regulation of cyclic nucleotides, cyclic-nucleotide-dependent protein kinases and one of their major substrates in human platelets. Estimating the rate of cAMP-regulated and cGMP-regulated protein phosphorylation in intact cells. Eur. J. Biochem.,  1992, 205(2), 471-481.
[http://dx.doi.org/10.1111/j.1432-1033.1992.tb16803.x] [PMID:  1315268] 
[120] 
Horstrup, K.; Jablonka, B.; Hönig-Liedl, P.; Just, M.; Kochsiek, K.; Walter, U. Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition. Eur. J. Biochem.,  1994, 225(1), 21-27.
[http://dx.doi.org/10.1111/j.1432-1033.1994.00021.x] [PMID:  7925440] 
[121] 
Wang, G.R.; Zhu, Y.; Halushka, P.V.; Lincoln, T.M.; Mendelsohn, M.E. Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase. Proc. Natl. Acad. Sci. USA,  1998, 95(9), 4888-4893.
[http://dx.doi.org/10.1073/pnas.95.9.4888] [PMID:  9560198] 
[122] 
Freedman, J.E.; Loscalzo, J.; Barnard, M.R.; Alpert, C.; Keaney, J.F.; Michelson, A.D. Nitric oxide released from activated platelets inhibits platelet recruitment. J. Clin. Invest.,  1997, 100(2), 350-356.
[http://dx.doi.org/10.1172/JCI119540] [PMID:  9218511] 
[123] 
Nimpf, J.; Wurm, H.; Kostner, G.M.; Kenner, T. Platelet activation in normo- and hyperlipoproteinemias. Basic Res. Cardiol.,  1986, 81(5), 437-453.
[http://dx.doi.org/10.1007/BF01907750] [PMID:  3026304] 
[124] 
Alexandru, N.; Constantin, A.; Popov, D. Carbonylation of platelet proteins occurs as consequence of oxidative stress and thrombin activation, and is stimulated by ageing and type 2 diabetes. Clin. Chem. Lab. Med.,  2008, 46(4), 528-536.
[http://dx.doi.org/10.1515/CCLM.2008.104] [PMID:  18302528] 
[125] 
de Meirelles, L.R. Resende, Ade.C.; Matsuura, C.; Salgado, A.; Pereira, N.R.; Cascarelli, P.G.; Mendes-Ribeiro, A.C.; Brunini, T.M. Platelet activation, oxidative stress and overexpression of inducible nitric oxide synthase in moderate heart failure. Clin. Exp. Pharmacol. Physiol.,  2011, 38(10), 705-710.
[http://dx.doi.org/10.1111/j.1440-1681.2011.05580.x] [PMID:  21806669] 
[126] 
Anfossi, G.; Russo, I.; Trovati, M. Platelet dysfunction in central obesity. Nutr. Metab. Cardiovasc. Dis.,  2009, 19(6), 440-449.
[http://dx.doi.org/10.1016/j.numecd.2009.01.006] [PMID:  19346117] 
[127] 
Takajo, Y.; Ikeda, H.; Haramaki, N.; Murohara, T.; Imaizumi, T. Augmented oxidative stress of platelets in chronic smokers. Mechanisms of impaired platelet-derived nitric oxide bioactivity and augmented platelet aggregability. J. Am. Coll. Cardiol.,  2001, 38(5), 1320-1327.
[http://dx.doi.org/10.1016/S0735-1097(01)01583-2] [PMID:  11691502] 
[128] 
Gkaliagkousi, E.; Ritter, J.; Ferro, A. Platelet-derived nitric oxide signaling and regulation. Circ. Res.,  2007, 101(7), 654-662.
[http://dx.doi.org/10.1161/CIRCRESAHA.107.158410] [PMID:  17901370] 
[129] 
Ichiki, K.; Ikeda, H.; Haramaki, N.; Ueno, T.; Imaizumi, T. Long-term smoking impairs platelet-derived nitric oxide release. Circulation,  1996, 94(12), 3109-3114.
[http://dx.doi.org/10.1161/01.CIR.94.12.3109] [PMID:  8989117] 
[130] 
Keaney, J.F., Jr Loscalzo, J. Diabetes, oxidative stress, and platelet activation. Circulation,  1999, 99(2), 189-191.
[http://dx.doi.org/10.1161/01.CIR.99.2.189] [PMID:  9892579] 
[131] 
Salvemini, D.; de Nucci, G.; Sneddon, J.M.; Vane, J.R. Superoxide anions enhance platelet adhesion and aggregation. Br. J. Pharmacol.,  1989, 97(4), 1145-1150.
[http://dx.doi.org/10.1111/j.1476-5381.1989.tb12572.x] [PMID:  2551440] 
[132] 
Bouloumié, A.; Bauersachs, J.; Linz, W.; Schölkens, B.A.; Wiemer, G.; Fleming, I.; Busse, R. Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension,  1997, 30(4), 934-941.
[http://dx.doi.org/10.1161/01.HYP.30.4.934] [PMID:  9336396] 
[133] 
Wolin, M.S. Interactions of oxidants with vascular signaling systems. Arterioscler. Thromb. Vasc. Biol.,  2000, 20(6), 1430-1442.
[http://dx.doi.org/10.1161/01.ATV.20.6.1430] [PMID:  10845855] 
[134] 
Ferroni, P.; Vazzana, N.; Riondino, S.; Cuccurullo, C.; Guadagni, F.; Davì, G. Platelet function in health and disease: from molecular mechanisms, redox considerations to novel therapeutic opportunities. Antioxid. Redox Signal.,  2012, 17(10), 1447-1485.
[http://dx.doi.org/10.1089/ars.2011.4324] [PMID:  22458931] 
[135] 
Gladwin, M.T. Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome. J. Clin. Invest.,  2006, 116(9), 2330-2332.
[http://dx.doi.org/10.1172/JCI29807] [PMID:  16955136] 
[136] 
Chirkov, Y.Y.; Horowitz, J.D. Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier? Pharmacol. Ther.,  2007, 116(2), 287-305.
[http://dx.doi.org/10.1016/j.pharmthera.2007.06.012] [PMID:  17765975] 
[137] 
Stasch, J.P.; Schmidt, P.M.; Nedvetsky, P.I.; Nedvetskaya, T.Y. H S, A.K.; Meurer, S.; Deile, M.; Taye, A.; Knorr, A.; Lapp, H.; Müller, H.; Turgay, Y.; Rothkegel, C.; Tersteegen, A.; Kemp-Harper, B.; Müller-Esterl, W.; Schmidt, H.H. Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J. Clin. Invest.,  2006, 116(9), 2552-2561.
[http://dx.doi.org/10.1172/JCI28371] [PMID:  16955146] 
[138] 
Brown, A.S.; Moro, M.A.; Masse, J.M.; Cramer, E.M.; Radomski, M.; Darley-Usmar, V. Nitric oxide-dependent and independent effects on human platelets treated with peroxynitrite. Cardiovasc. Res.,  1998, 40(2), 380-388.
[http://dx.doi.org/10.1016/S0008-6363(98)00182-5] [PMID:  9893732] 
[139] 
Shah, A.; Passacquale, G.; Gkaliagkousi, E.; Ritter, J.; Ferro, A. Platelet nitric oxide signalling in heart failure: role of oxidative stress. Cardiovasc. Res.,  2011, 91(4), 625-631.
[http://dx.doi.org/10.1093/cvr/cvr115] [PMID:  21502370] 
[140] 
Ozüyaman, B.; Gödecke, A.; Küsters, S.; Kirchhoff, E.; Scharf, R.E.; Schrader, J. Endothelial nitric oxide synthase plays a minor role in inhibition of arterial thrombus formation. Thromb. Haemost.,  2005, 93(6), 1161-1167.
[http://dx.doi.org/10.1160/TH03-09-0588] [PMID:  15968403] 
[141] 
Iafrati, M.D.; Vitseva, O.; Tanriverdi, K.; Blair, P.; Rex, S.; Chakrabarti, S.; Varghese, S.; Freedman, J.E. Compensatory mechanisms influence hemostasis in setting of eNOS deficiency. Am. J. Physiol. Heart Circ. Physiol.,  2005, 288(4), H1627-H1632.
[http://dx.doi.org/10.1152/ajpheart.00819.2004] [PMID:  15563534] 
[142] 
Gryglewski, R.J. Prostacyclin among prostanoids. Pharmacol. Rep.,  2008, 60(1), 3-11.
[PMID:  18276980] 
[143] 
Taylor, L.; Menconi, M.J.; Polgar, P. The participation of hydroperoxides and oxygen radicals in the control of prostaglandin synthesis. J. Biol. Chem.,  1983, 258(11), 6855-6857.
[PMID:  6406491] 
[144] 
Ambrosio, G.; Golino, P.; Pascucci, I.; Rosolowsky, M.; Campbell, W.B.; DeClerck, F.; Tritto, I.; Chiariello, M. Modulation of platelet function by reactive oxygen metabolites. Am. J. Physiol.,  1994, 267(1 Pt 2), H308-H318.
[PMID:  8048596] 
[145] 
Iuliano, L.; Praticò, D.; Bonavita, M.S.; Violi, F. Involvement of phospholipase A(2) in H(2)O(2)-dependent platelet activation. Platelets,  1992, 3(2), 87-90.
[http://dx.doi.org/10.3109/09537109209003393] [PMID:  21043868] 
[146] 
Hashizume, T.; Yamaguchi, H.; Kawamoto, A.; Tamura, A.; Sato, T.; Fujii, T. Lipid peroxide makes rabbit platelet hyperaggregable to agonists through phospholipase A2 activation. Arch. Biochem. Biophys.,  1991, 289(1), 47-52.
[http://dx.doi.org/10.1016/0003-9861(91)90440-T] [PMID:  1910316] 
[147] 
Hornberger, W.; Patscheke, H. Primary stimuli of icosanoid release inhibit arachidonoyl-CoA synthetase and lysophospholipid acyltransferase. Mechanism of action of hydrogen peroxide and methyl mercury in platelets. Eur. J. Biochem.,  1990, 187(1), 175-181.
[http://dx.doi.org/10.1111/j.1432-1033.1990.tb15292.x] [PMID:  2105213] 
[148] 
Jardin, I.; Ben Amor, N.; Hernández-Cruz, J.M.; Salido, G.M.; Rosado, J.A. Involvement of SNARE proteins in thrombin-induced platelet aggregation: evidence for the relevance of Ca2+ entry. Arch. Biochem. Biophys.,  2007, 465(1), 16-25.
[http://dx.doi.org/10.1016/j.abb.2007.04.038] [PMID:  17543880] 
[149] 
Li, Y.; Woo, V.; Bose, R. Platelet hyperactivity and abnormal Ca(2+) homeostasis in diabetes mellitus. Am. J. Physiol. Heart Circ. Physiol.,  2001, 280(4), H1480-H1489.
[http://dx.doi.org/10.1152/ajpheart.2001.280.4.H1480] [PMID:  11247757] 
[150] 
López, J.J.; Camello-Almaraz, C.; Pariente, J.A.; Salido, G.M.; Rosado, J.A. Ca2+ accumulation into acidic organelles mediated by Ca2+- and vacuolar H+-ATPases in human platelets. Biochem. J.,  2005, 390(Pt 1), 243-252.
[http://dx.doi.org/10.1042/BJ20050168] [PMID:  15847604] 
[151] 
Rosado, J.A.; Sage, S.O. The ERK cascade, a new pathway involved in the activation of store-mediated calcium entry in human platelets. Trends Cardiovasc. Med.,  2002, 12(5), 229-234.
[http://dx.doi.org/10.1016/S1050-1738(02)00161-5] [PMID:  12161078] 
[152] 
Mirabelli, F.; Salis, A.; Vairetti, M.; Bellomo, G.; Thor, H.; Orrenius, S. Cytoskeletal alterations in human platelets exposed to oxidative stress are mediated by oxidative and Ca2+-dependent mechanisms. Arch. Biochem. Biophys.,  1989, 270(2), 478-488.
[http://dx.doi.org/10.1016/0003-9861(89)90529-8] [PMID:  2539775] 
[153] 
Redondo, P.C.; Salido, G.M.; Rosado, J.A.; Pariente, J.A. Effect of hydrogen peroxide on Ca2+ mobilisation in human platelets through sulphydryl oxidation dependent and independent mechanisms. Biochem. Pharmacol.,  2004, 67(3), 491-502.
[http://dx.doi.org/10.1016/j.bcp.2003.09.031] [PMID:  15037201] 
[154] 
Clark, E.A.; Brugge, J.S. Tyrosine phosphorylation in platelets potential roles in intracellular signal transduction. Trends Cardiovasc. Med.,  1993, 3(6), 218-227.
[http://dx.doi.org/10.1016/1050-1738(93)90043-6] [PMID:  21244912] 
[155] 
Clark, E.A.; Shattil, S.J.; Brugge, J.S. Regulation of protein tyrosine kinases in platelets. Trends Biochem. Sci.,  1994, 19(11), 464-469.
[http://dx.doi.org/10.1016/0968-0004(94)90131-7] [PMID:  7855888] 
[156] 
Hernández-Hernández, A.; Sánchez-Yagüe, J.; Martín-Valmaseda, E.M.; Llanillo, M. Oxidative inactivation of human and sheep platelet membrane-associated phosphotyrosine phosphatase activity. Free Radic. Biol. Med.,  1999, 26(9-10), 1218-1230.
[http://dx.doi.org/10.1016/S0891-5849(98)00306-2] [PMID:  10381193] 
[157] 
Irani, K.; Pham, Y.; Coleman, L.D.; Roos, C.; Cooke, G.E.; Miodovnik, A.; Karim, N.; Wilhide, C.C.; Bray, P.F.; Goldschmidt-Clermont, P.J. Priming of platelet alphaIIbbeta3 by oxidants is associated with tyrosine phosphorylation of beta3. Arterioscler. Thromb. Vasc. Biol.,  1998, 18(11), 1698-1706.
[http://dx.doi.org/10.1161/01.ATV.18.11.1698] [PMID:  9812907] 
[158] 
Golden, A.; Brugge, J.S.; Shattil, S.J. Role of platelet membrane glycoprotein IIb-IIIa in agonist-induced tyrosine phosphorylation of platelet proteins. J. Cell Biol.,  1990, 111(6 Pt 2), 3117-3127.
[http://dx.doi.org/10.1083/jcb.111.6.3117] [PMID:  1702789] 
[159] 
Nagai, K.; Inazu, T.; Yamamura, H. p72syk is activated by vanadate plus H2O2 in porcine platelets and phosphorylates GTPase activating protein on tyrosine residue(s). J. Biochem.,  1994, 116(5), 1176-1181.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a124646] [PMID:  7896750] 
[160] 
Jang, J.Y.; Min, J.H.; Chae, Y.H.; Baek, J.Y.; Wang, S.B.; Park, S.J.; Oh, G.T.; Lee, S.H.; Ho, Y.S.; Chang, T.S. Reactive oxygen species play a critical role in collagen-induced platelet activation via SHP-2 oxidation. Antioxid. Redox Signal.,  2014, 20(16), 2528-2540.
[http://dx.doi.org/10.1089/ars.2013.5337] [PMID:  24093153] 
[161] 
Fialkow, L.; Chan, C.K.; Grinstein, S.; Downey, G.P. Regulation of tyrosine phosphorylation in neutrophils by the NADPH oxidase. Role of reactive oxygen intermediates. J. Biol. Chem.,  1993, 268(23), 17131-17137.
[PMID:  8349602] 
[162] 
Förstermann, U. Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat. Clin. Pract. Cardiovasc. Med.,  2008, 5(6), 338-349.
[http://dx.doi.org/10.1038/ncpcardio1211] [PMID:  18461048] 
[163] 
Halliwell, B. Biochemistry of oxidative stress. Biochem. Soc. Trans.,  2007, 35(Pt 5), 1147-1150.
[http://dx.doi.org/10.1042/BST0351147] [PMID:  17956298] 
[164] 
Vucinic, L.; Singh, I.; Spargo, F.J.; Hawley, J.A.; Linden, M.D. Gamma tocopherol supplementation prevents exercise induced coagulation and platelet aggregation. Thromb. Res.,  2010, 125(2), 196-199.
[http://dx.doi.org/10.1016/j.thromres.2009.11.015] [PMID:  20004007] 
[165] 
Fleming, I.; Fisslthaler, B.; Dimmeler, S.; Kemp, B.E.; Busse, R. Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ. Res.,  2001, 88(11), E68-E75.
[http://dx.doi.org/10.1161/hh1101.092677] [PMID:  11397791] 
[166] 
Freedman, J.E.; Li, L.; Sauter, R.; Keaney, J.F. J.R. alpha-Tocopherol and protein kinase C inhibition enhance platelet-derived nitric oxide release. FASEB J.,  2000, 14(15), 2377-2379.
[http://dx.doi.org/10.1096/fj.00-0360fje] [PMID:  11024007] 
[167] 
Silbert, P.L.; Leong, L.L.; Sturm, M.J.; Strophair, J.; Taylor, R.R. Short term vitamin E supplementation has no effect on platelet function, plasma phospholipase A2 and lyso-PAF in male volunteers. Clin. Exp. Pharmacol. Physiol.,  1990, 17(9), 645-651.
[http://dx.doi.org/10.1111/j.1440-1681.1990.tb01365.x] [PMID:  2279352] 
[168] 
Kockmann, V.; Vericel, E.; Croset, M.; Lagarde, M. Vitamin E fails to alter the aggregation and the oxygenated metabolism of arachidonic acid in normal human platelets. Prostaglandins,  1988, 36(5), 607-620.
[http://dx.doi.org/10.1016/0090-6980(88)90007-X] [PMID:  3148963] 
[169] 
Hamelin, S.S.; Chan, A.C. Modulation of platelet thromboxane and malonaldehyde by dietary vitamin E and linoleate. Lipids,  1983, 18(3), 267-269.
[http://dx.doi.org/10.1007/BF02534560] [PMID:  6855486] 
[170] 
Karpen, C.W.; Merola, A.J.; Trewyn, R.W.; Cornwell, D.G.; Panganamala, R.V. Modulation of platelet thromboxane A2 and arterial prostacyclin by dietary vitamin E. Prostaglandins,  1981, 22(4), 651-661.
[http://dx.doi.org/10.1016/0090-6980(81)90074-5] [PMID:  6798639] 
[171] 
Pritchard, K.A.; Greco, N.J.; Panganamala, R.V. Effect of dietary vitamin E on the production of platelet 12-hydroxyeicosatetraenoic acid (12-HETE). Thromb. Haemost.,  1986, 55(1), 6-7.
[http://dx.doi.org/10.1055/s-0038-1661435] [PMID:  3705009] 
[172] 
Gökkusu, C.; Palanduz, S.; Ademoğlu, E.; Tamer, S. Oxidant and antioxidant systems in niddm patients: influence of vitamin E supplementation. Endocr. Res.,  2001, 27(3), 377-386.
[http://dx.doi.org/10.1081/ERC-100106015] [PMID:  11678585] 
[173] 
Gisinger, C.; Jeremy, J.; Speiser, P.; Mikhailidis, D.; Dandona, P.; Schernthaner, G. Effect of vitamin E supplementation on platelet thromboxane A2 production in type I diabetic patients. Double-blind crossover trial. Diabetes,  1988, 37(9), 1260-1264.
[http://dx.doi.org/10.2337/diab.37.9.1260] [PMID:  3044891] 
[174] 
Watanabe, J.; Umeda, F.; Wakasugi, H.; Ibayashi, H. Effect of vitamin E on platelet aggregation in diabetes mellitus. Thromb. Haemost.,  1984, 51(3), 313-316.
[http://dx.doi.org/10.1055/s-0038-1661090] [PMID:  6495252] 
[175] 
Jain, S.K.; Krueger, K.S.; McVie, R.; Jaramillo, J.J.; Palmer, M.; Smith, T. Relationship of blood thromboxane-B2 (TxB2) with lipid peroxides and effect of vitamin E and placebo supplementation on TxB2 and lipid peroxide levels in type 1 diabetic patients. Diabetes Care,  1998, 21(9), 1511-1516.
[http://dx.doi.org/10.2337/diacare.21.9.1511] [PMID:  9727900] 
[176] 
Padayatty, S.J.; Katz, A.; Wang, Y.; Eck, P.; Kwon, O.; Lee, J.H.; Chen, S.; Corpe, C.; Dutta, A.; Dutta, S.K.; Levine, M. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J. Am. Coll. Nutr.,  2003, 22(1), 18-35.
[http://dx.doi.org/10.1080/07315724.2003.10719272] [PMID:  12569111] 
[177] 
Frei, B. Reactive oxygen species and antioxidant vitamins: mechanisms of action. Am. J. Med.,  1994, 97(3A), 5S-13S.
[http://dx.doi.org/10.1016/0002-9343(94)90292-5] [PMID:  8085584] 
[178] 
Haramaki, N.; Stewart, D.B.; Aggarwal, S.; Ikeda, H.; Reznick, A.Z.; Packer, L. Networking antioxidants in the isolated rat heart are selectively depleted by ischemia-reperfusion. Free Radic. Biol. Med.,  1998, 25(3), 329-339.
[http://dx.doi.org/10.1016/S0891-5849(98)00066-5] [PMID:  9680179] 
[179] 
Meister, A. Glutathione-ascorbic acid antioxidant system in animals. J. Biol. Chem.,  1994, 269(13), 9397-9400.
[PMID:  8144521] 
[180] 
Cordova, C.; Musca, A.; Violi, F.; Perrone, A.; Alessandri, C. Influence of ascorbic acid on platelet aggregation in vitro and in vivo. Atherosclerosis,  1982, 41(1), 15-19.
[http://dx.doi.org/10.1016/0021-9150(82)90064-8] [PMID:  7073791] 
[181] 
Bayard, V.; Chamorro, F.; Motta, J.; Hollenberg, N.K. Does flavanol intake influence mortality from nitric oxide-dependent processes? Ischemic heart disease, stroke, diabetes mellitus, and cancer in Panama. Int. J. Med. Sci.,  2007, 4(1), 53-58.
[http://dx.doi.org/10.7150/ijms.4.53] [PMID:  17299579] 
[182] 
Buijsse, B.; Feskens, E.J.; Kok, F.J.; Kromhout, D. Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study. Arch. Intern. Med.,  2006, 166(4), 411-417.
[http://dx.doi.org/10.1001/archinte.166.4.411] [PMID:  16505260] 
[183] 
Hertog, M.G.; Feskens, E.J.; Hollman, P.C.; Katan, M.B.; Kromhout, D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet,  1993, 342(8878), 1007-1011.
[http://dx.doi.org/10.1016/0140-6736(93)92876-U] [PMID:  8105262] 
[184] 
Arts, I.C.; Hollman, P.C.; Feskens, E.J.; Bueno de Mesquita, H.B.; Kromhout, D. Catechin intake might explain the inverse relation between tea consumption and ischemic heart disease: the Zutphen Elderly Study. Am. J. Clin. Nutr.,  2001, 74(2), 227-232.
[http://dx.doi.org/10.1093/ajcn/74.2.227] [PMID:  11470725] 
[185] 
El Haouari, M.; Rosado, J.A. Modulation of platelet function and signaling by flavonoids. Mini Rev. Med. Chem.,  2011, 11(2), 131-142.
[http://dx.doi.org/10.2174/138955711794519537] [PMID:  21222578] 
[186] 
Pignatelli, P.; Di Santo, S.; Buchetti, B.; Sanguigni, V.; Brunelli, A.; Violi, F. Polyphenols enhance platelet nitric oxide by inhibiting protein kinase C-dependent NADPH oxidase activation: effect on platelet recruitment. FASEB J.,  2006, 20(8), 1082-1089.
[http://dx.doi.org/10.1096/fj.05-5269com] [PMID:  16770007] 
[187] 
Pignatelli, P.; Ghiselli, A.; Buchetti, B.; Carnevale, R.; Natella, F.; Germanò, G.; Fimognari, F.; Di Santo, S.; Lenti, L.; Violi, F. Polyphenols synergistically inhibit oxidative stress in subjects given red and white wine. Atherosclerosis,  2006, 188(1), 77-83.
[http://dx.doi.org/10.1016/j.atherosclerosis.2005.10.025] [PMID:  16310197] 
[188] 
Flammer, A.J.; Hermann, F.; Sudano, I.; Spieker, L.; Hermann, M.; Cooper, K.A.; Serafini, M.; Lüscher, T.F.; Ruschitzka, F.; Noll, G.; Corti, R. Dark chocolate improves coronary vasomotion and reduces platelet reactivity. Circulation,  2007, 116(21), 2376-2382.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.713867] [PMID:  17984375] 
[189] 
Hermann, F.; Spieker, L.E.; Ruschitzka, F.; Sudano, I.; Hermann, M.; Binggeli, C.; Lüscher, T.F.; Riesen, W.; Noll, G.; Corti, R. Dark chocolate improves endothelial and platelet function. Heart,  2006, 92(1), 119-120.
[http://dx.doi.org/10.1136/hrt.2005.063362] [PMID:  16365364] 
[190] 
Carnevale, R.; Pignatelli, P.; Nocella, C.; Loffredo, L.; Pastori, D.; Vicario, T.; Petruccioli, A.; Bartimoccia, S.; Violi, F. Extra virgin olive oil blunt post-prandial oxidative stress via NOX2 down-regulation. Atherosclerosis,  2014, 235(2), 649-658.
[http://dx.doi.org/10.1016/j.atherosclerosis.2014.05.954] [PMID:  24980290] 
[191] 
Calderón-Montaño, J.M.; Burgos-Morón, E.; Pérez-Guerrero, C.; López-Lázaro, M. A review on the dietary flavonoid kaempferol. Mini Rev. Med. Chem.,  2011, 11(4), 298-344.
[http://dx.doi.org/10.2174/138955711795305335] [PMID:  21428901] 
[192] 
Olszewska, M. Separation of quercetin, sexangularetin, kaempferol and isorhamnetin for simultaneous HPLC determination of flavonoid aglycones in inflorescences, leaves and fruits of three Sorbus species. J. Pharm. Biomed. Anal.,  2008, 48(3), 629-635.
[http://dx.doi.org/10.1016/j.jpba.2008.06.004] [PMID:  18635332] 
[193] 
Wang, Y.; Zhang, G.; Pan, J.; Gong, D. Novel insights into the inhibitory mechanism of kaempferol on xanthine oxidase. J. Agric. Food Chem.,  2015, 63(2), 526-534.
[http://dx.doi.org/10.1021/jf505584m] [PMID:  25539132] 
[194] 
Bertelli, A.A.; Giovannini, L.; Bernini, W.; Migliori, M.; Fregoni, M.; Bavaresco, L.; Bertelli, A. Antiplatelet activity of cis-resveratrol. Drugs Exp. Clin. Res.,  1996, 22(2), 61-63.
[PMID:  8998912] 
[195] 
Jang, M.; Cai, L.; Udeani, G.O.; Slowing, K.V.; Thomas, C.F.; Beecher, C.W.; Fong, H.H.; Farnsworth, N.R.; Kinghorn, A.D.; Mehta, R.G.; Moon, R.C.; Pezzuto, J.M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science,  1997, 275(5297), 218-220.
[http://dx.doi.org/10.1126/science.275.5297.218] [PMID:  8985016] 
[196] 
Lin, J.K.; Tsai, S.H. Chemoprevention of cancer and cardiovascular disease by resveratrol. Proc. Natl. Sci. Counc. Repub. China B,  1999, 23(3), 99-106.
[PMID:  10492890] 
[197] 
Olas, B.; Zbikowska, H.M.; Wachowicz, B.; Krajewski, T.; Buczyński, A.; Magnuszewska, A. Inhibitory effect of resveratrol on free radical generation in blood platelets. Acta Biochim. Pol.,  1999, 46(4), 961-966.
[PMID:  10824865] 
[198] 
Zbikowska, H.M.; Olas, B.; Wachowicz, B.; Krajewski, T. Response of blood platelets to resveratrol. Platelets,  1999, 10(4), 247-252.
[http://dx.doi.org/10.1080/09537109976103] [PMID:  16801100] 
[199] 
Olas, B.; Wachowicz, B. Resveratrol, a phenolic antioxidant with effects on blood platelet functions. Platelets,  2005, 16(5), 251-260.
[http://dx.doi.org/10.1080/09537100400020591] [PMID:  16011975] 
[200] 
Spanier, G.; Xu, H.; Xia, N.; Tobias, S.; Deng, S.; Wojnowski, L.; Forstermann, U.; Li, H. Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4). J. Physiol. Pharmacol.,  2009, 60(Suppl. 4), 111-116.
[PMID:  20083859] 
[201] 
Wallerath, T.; Deckert, G.; Ternes, T.; Anderson, H.; Li, H.; Witte, K.; Förstermann, U. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation,  2002, 106(13), 1652-1658.
[http://dx.doi.org/10.1161/01.CIR.0000029925.18593.5C] [PMID:  12270858] 
[202] 
Arunachalam, G.; Yao, H.; Sundar, I.K.; Caito, S.; Rahman, I. SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: Role of resveratrol. Biochem. Biophys. Res. Commun.,  2010, 393(1), 66-72.
[http://dx.doi.org/10.1016/j.bbrc.2010.01.080] [PMID:  20102704] 
[203] 
Schmitt, C.A.; Dirsch, V.M. Modulation of endothelial nitric oxide by plant-derived products. Nitric Oxide,  2009, 21(2), 77-91.
[http://dx.doi.org/10.1016/j.niox.2009.05.006] [PMID:  19497380] 
[204] 
Yuan, Q.; Peng, J.; Liu, S.Y.; Wang, C.J.; Xiang, D.X.; Xiong, X.M.; Hu, C.P.; Li, Y.J. Inhibitory effect of resveratrol derivative BTM-0512 on high glucose-induced cell senescence involves dimethylaminohydrolase/asymmetric dimethylarginine pathway. Clin. Exp. Pharmacol. Physiol.,  2010, 37(5-6), 630-635.
[http://dx.doi.org/10.1111/j.1440-1681.2010.05368.x] [PMID:  20132235] 
[205] 
El Haouari, M.; Rosado, J.A. Medicinal plants with antiplatelet activity. Phytother. Res.,  2016, 30(7), 1059-1071.
[http://dx.doi.org/10.1002/ptr.5619] [PMID:  27062716] 
[206] 
Choi, S.S.; Cha, B.Y.; Lee, Y.S.; Yonezawa, T.; Teruya, T.; Nagai, K.; Woo, J.T. Magnolol enhances adipocyte differentiation and glucose uptake in 3T3-L1 cells. Life Sci.,  2009, 84(25-26), 908-914.
[http://dx.doi.org/10.1016/j.lfs.2009.04.001] [PMID:  19376135] 
[207] 
el-Feraly, F.S.; Chan, Y.M. Isolation and characterization of the sesquiterpene lactones costunolide, parthenolide, costunolide diepoxide, santamarine, and reynosin from Magnolia grandiflora L. J. Pharm. Sci.,  1978, 67(3), 347-350.
[http://dx.doi.org/10.1002/jps.2600670319] [PMID:  641720] 
[208] 
Shen, C.C.; Ni, C.L.; Shen, Y.C.; Huang, Y.L.; Kuo, C.H.; Wu, T.S.; Chen, C.C. Phenolic constituents from the stem bark of Magnolia officinalis. J. Nat. Prod.,  2009, 72(1), 168-171.
[http://dx.doi.org/10.1021/np800494e] [PMID:  19086868] 
[209] 
Chang, C.C.; Lu, W.J.; Chiang, C.W.; Jayakumar, T.; Ong, E.T.; Hsiao, G.; Fong, T.H.; Chou, D.S.; Sheu, J.R. Potent antiplatelet activity of sesamol in an in vitro and in vivo model: pivotal roles of cyclic AMP and p38 mitogen-activated protein kinase. J. Nutr. Biochem.,  2010, 21(12), 1214-1221.
[http://dx.doi.org/10.1016/j.jnutbio.2009.10.009] [PMID:  20015631] 
[210] 
Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Klotz, K.N.; Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev.,  2001, 53(4), 527-552.
[PMID:  11734617] 
[211] 
Johnston-Cox, H.A.; Ravid, K. Adenosine and blood platelets. Purinergic Signal.,  2011, 7(3), 357-365.
[http://dx.doi.org/10.1007/s11302-011-9220-4] [PMID:  21484090] 
[212] 
Fairweather-Tait, S.J.; Bao, Y.; Broadley, M.R.; Collings, R.; Ford, D.; Hesketh, J.E.; Hurst, R. Selenium in human health and disease. Antioxid. Redox Signal.,  2011, 14(7), 1337-1383.
[http://dx.doi.org/10.1089/ars.2010.3275] [PMID:  20812787] 
[213] 
Ronai, Z.; Tillotson, J.K.; Traganos, F.; Darzynkiewicz, Z.; Conaway, C.C.; Upadhyaya, P.; el-Bayoumy, K. Effects of organic and inorganic selenium compounds on rat mammary tumor cells. Int. J. Cancer,  1995, 63(3), 428-434.
[http://dx.doi.org/10.1002/ijc.2910630322] [PMID:  7591244] 
[214] 
Low, S.C.; Berry, M.J. Knowing when not to stop: selenocysteine incorporation in eukaryotes. Trends Biochem. Sci.,  1996, 21(6), 203-208.
[http://dx.doi.org/10.1016/S0968-0004(96)80016-8] [PMID:  8744353] 
[215] 
Guidi, G.; Schiavon, R.; Biasioli, A.; Perona, G. The enzyme glutathione peroxidase in arachidonic acid metabolism of human platelets. J. Lab. Clin. Med.,  1984, 104(4), 574-582.
[PMID:  6434676] 
[216] 
Zbikowska, H.M.; Wachowicz, B.; Krajewski, T. Comparative effects of selenite and selenite on the glutathione-related enzymes activity in pig blood platelets. Biol. Trace Elem. Res.,  1997, 57(3), 259-269.
[http://dx.doi.org/10.1007/BF02785294] [PMID:  9359992] 
[217] 
Freedman, J.E. Oxidative stress and platelets. Arterioscler. Thromb. Vasc. Biol.,  2008, 28(3), s11-s16.
[http://dx.doi.org/10.1161/ATVBAHA.107.159178] [PMID:  18174453] 
[218] 
de Gaetano, G. Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet,  2001, 357(9250), 89-95.
[http://dx.doi.org/10.1016/S0140-6736(00)03539-X] [PMID:  11197445] 
[219] 
Yusuf, S.; Dagenais, G.; Pogue, J.; Bosch, J.; Sleight, P. Vitamin E supplementation and cardiovascular events in high-risk patients. Heart outcomes prevention evaluation study investigators. N. Engl. J. Med.,  2000, 342(3), 154-160.
[http://dx.doi.org/10.1056/NEJM200001203420302] [PMID:  10639540] 
Cite As
Current Medicinal Chemistry

Platelet Oxidative Stress and its Relationship with Cardiovascular Diseases in Type 2 Diabetes Mellitus Patients

Abstract
