Antiinflammatory effects of aspirin in ACS: relevant to its cardio coronary actions?

Summary

Vascular injury in acute coronary syndromes (ACS) involves a complex cross-talk between inflammatory mediators, platelets and thrombosis, where the interaction between platelets and coagulation factors (e. g. thrombin) is a central link between thrombosis and inflammation. In ACS, aspirin at antiplatelet doses exhibits anti-inflammatory effects as seen from the decrease in inflammation markers such as CRP, M-CSF, MCP-1 and others. These actions probably occur subsequent to inhibition of platelet COX-1-dependent thromboxane formation and its action as a multipotent autocrine and paracrine agent. This likely involves inhibition of thrombin formation as well as inhibition of secondary pro-inflammatory mediators, such as sphingosine-1-phosphate. Experimental and limited clinical data additionally suggest antiinflammatory effects of aspirin independent of its antiplatelet action. For example, aspirin at antiplatelet doses might acetylate COX-2 in vascular cells, directing the activity of the enzyme into a 15-lipoxygenase which by transcellular metabolism results in the formation of 15-epi-lipoxin (‘aspirin-triggered lipoxin’), an antiinflammatory mediator. Furthermore, aspirin stimulates eNOS via lysine-acetylation, eventually resulting in induction of heme oxygenase (HO-1), which improves the antioxidative potential of vascular cells. All of these effects have been seen at antiplatelet doses of 100–300 mg/day, equivalent to peak plasma levels of 10–30 μM. Many more potentially antiinflammatory mechanisms of aspirin have been described, mostly salicy-late-related, at low to medium millimolar concentrations and, therefore, are of minor clinical interest. Altogether, there is a wealth of data supporting antiiflammatory effects of aspirin in ACS, but studies generating direct evidence for antiinflammatory effects in ACS remain to be done.

Keywords

Aspirin - platelet pharmacology - thromboxane - inflammatory mediators - thrombin

• References

• 1 Hohlfeld T, Schrör K. Aspirin. In: Antiplatelet Therapy. Wiley: 2014. pp. 111-116.
• 2 Morris T. et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol 2009; 183: 2089-2096.
• 3 Ikonomidis I. et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999; 100: 793-798.
• 4 Kennon S. et al. The effect of aspirin on C-reactive protein as a marker of risk in unstable angina. J Am Coll Cardiol 2001; 37: 1266-1270.
• 5 Ridker PM. et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-979.
• 6 Ridker PM. et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998; 98: 731-733.
• 7 Muhlestein JB. Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost 2010; 103: 71-82.
• 8 Ulrych T. et al. Release of sphingosine-1-phosphate from human platelets is dependent on thromboxane formation. J Thromb Haemost 2011; 09: 790-798.
• 9 Polzin A. et al. Aspirin inhibits release of platelet-derived sphingosine-1-phosphate in acute myocardial infarction. Int J Cardiol 2013; 170: e23-24.
• 10 Passacquale G, Ferro A. Current concepts of platelet activation: possibilities for therapeutic modulation of heterotypic vs. homotypic aggregation. Br J Clin Pharmacol 2011; 72: 604-618.
• 11 Weyrich AS. et al. The evolving role of platelets in inflammation. J Thromb Hae-most 2003; 01: 1897-1905.
• 12 Libby P. et al. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 2014; 114: 1867-1879.
• 13 Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685-1695.
• 14 Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005; 111: 3481-3488.
• 15 Langer HF. et al. Interaction of platelets and inflammatory endothelium in the development and progression of coronary artery disease. Semin Thromb He-most 2010; 36: 131-138.
• 16 Zimmerman GA, Weyrich AS. Signal-dependent protein synthesis by activated platelets: new pathways to altered phenotype and function. Arterioscler Thromb Vasc Biol 2008; 28: s17-24.
• 17 Gawaz M. et al. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
• 18 Brummel KE. et al. Thrombin functions during tissue factor-induced blood coagulation. Blood 2002; 100: 148-152.
• 19 Alexander KS. et al. Role of electrostatic interactions in binding of thrombin to the fibrinogen gamma’ chain. Biochemistry 2012; 51: 3445-3450.
• 20 Kalz J. et al. Thrombin generation and atherosclerosis. J Thromb Thrombolysis 2014; 37: 45-55.
• 21 Popovic M. et al. Thrombin and vascular inflammation. Mol Cell Biochem 2012; 359: 301-313.
• 22 Domsalla A, Melzig MF. Enhancement of protease-induced IL-6 release in monocytic U-937 cells by phorbol-12-myristate-13-acetate. Inflamm Res 2012; 61: 1125-1129.
• 23 Gawaz M. et al. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 2000; 148: 75-85.
• 24 Yasu T. et al. Effects of aspirin DL-lysine on thrombin generation in unstable an-gina pectoris. Am J Cardiol 1993; 71: 1164-1168.
• 25 Merlini PA. et al. Persistent activation of coagulation mechanism in unstable an-gina and myocardial infarction. Circulation 1994; 90: 61-68.
• 26 Ardissino D. et al. Coagulation activation and long-term outcome in acute coronary syndromes. Blood 2003; 102: 2731-2735.
• 27 Capra V. et al. Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation. J Thromb Hae-most 2014; 12: 126-137.
• 28 Gabrielsen A. et al. Thromboxane synthase expression and thromboxane A2 production in the atherosclerotic lesion. J Mol Med 2010; 88: 795-806.
• 29 Cherdon C. et al. BM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase. Prostaglandins Other Lipid Mediat 2011; 94: 124-132.
• 30 Petri MH. et al. Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun 2013; 441: 393-398.
• 31 Eikelboom JW. et al. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation 2008; 118: 1705-1712.
• 32 Matsuura E. et al. On aspirin treatment but not baseline thromboxane B2 levels predict adverse outcomes in patients with acute coronary syndromes. J Thromb Haemost 2012; 10: 1949-1951.
• 33 Rauch BH. Sphingosine 1-phosphate as a link between blood coagulation and inflammation. Cell Physiol Biochem 2014; 34: 185-196.
• 34 Takeya H. et al. Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells. Blood 2003; 102: 1693-1700.
• 35 Ulrych T. et al. Release of sphingosine-1-phosphate from human platelets is dependent on thromboxane formation. J Thromb Haemost 2011; 09: 790-798.
• 36 Gude DR. et al. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J 2008; 22: 2629-2638.
• 37 Mahajan-Thakur S. et al. Sphingosine-1-phosphate induces thrombin receptor PAR-4 expression to enhance cell migration and COX-2 formation in human monocytes. J Leukoc Biol 2014; 96: 611-618.
• 38 Santilli F. et al. Circulating myeloid-related protein-8/14 is related to thromboxane-dependent platelet activation in patients with acute coronary syndrome, with and without ongoing low-dose aspirin treatment. J Am Heart Assoc 2014; 03: 1-13.
• 39 Valgimigli M. et al. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc Interv 2012; 05: 268-277.
• 40 Montalescot G. et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014; 371: 1016-1027.
• 41 Szczeklik A. et al. Antiplatelet Drugs and Generation of Thrombin in Clotting Blood. Blood 1992; 80: 2006-2011.
• 42 Kessels H. et al. Measurement of thrombin generation in whole blood--the effect of heparin and aspirin. Thromb Haemost 1994; 72: 78-83.
• 43 Undas A. et al. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007; 109: 2285-2292.
• 44 Wallen NH, Ladjevardi M. Influence of low- and high-dose aspirin treatment on thrombin generation in whole blood. Thromb Res 1998; 92: 189-194.
• 45 Wolzt M. et al. Open-label, randomized study of the effect of rivaroxaban with or without acetylsalicylic acid on thrombus formation in a perfusion chamber. Thromb Res 2013; 132: 240-247.
• 46 Undas A. et al. Lack of aspirin-induced decrease in thrombin formation in subjects resistant to aspirin. Thromb Haemost 2007; 97: 1056-1058.
• 47 Schrör K. et al. Functional testing methods for the antiplatelet effects of aspirin. Biomark Med 2011; 05: 31-42.
• 48 Berk BC. et al. Elevation of C-reactive protein in “active” coronary artery disease. Am J Cardiol 1990; 65: 168-172.
• 49 de Beer FC. et al. Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J 1982; 47: 239-243.
• 50 Pietila K. et al. Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy. Eur Heart J 1993; 14: 915-919.
• 51 Liuzzo G. et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994; 331: 417-424.
• 52 Soejima H. et al. Aspirin possibly reduces cerebrovascular events in type 2 diabetic patients with higher C-reactive protein level: subanalysis from the JPAD trial. J Cardiol 2013; 62: 165-170.
• 53 Ridker PM. Inflammation, C-reactive protein, and cardiovascular disease: moving past the marker versus mediator debate. Circ Res 2014; 114: 594-595.
• 54 Grinstein J, Cannon CP. Aspirin resistance: Current status and role of tailored therapy. Clin Cardiol 2012; 35: 673-681.
• 55 Floyd CN, Ferro A. Mechanisms of aspirin resistance. Pharmacol Ther 2014; 141: 69-78.
• 56 Feng D. et al. Effect of short-term aspirin use on C-reactive protein. J Thromb Thrombolysis 2000; 09: 37-41.
• 57 Feldman M. et al. Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a placebo-controlled study using a highly sensitive C-reactive protein assay. J Am Coll Cardiol 2001; 37: 2036-2041.
• 58 Azar RR. et al. Effects of aspirin (325 mg/day) on serum high-sensitivity C-reactive protein, cytokines, and adhesion molecules in healthy volunteers. Am J Cardiol 2003; 92: 236-239.
• 59 Hovens MM. et al. Effects of aspirin on serum C-reactive protein and interleukin-6 levels in patients with type 2 diabetes without cardiovascular disease: a randomized placebo-controlled crossover trial. Diabetes Obes Metab 2008; 10: 668-674.
• 60 Kim MA. et al. The effect of aspirin on C-reactive protein in hypertensive patients. Clin Exp Hypertens 2011; 33: 47-52.
• 61 Rogowski O. et al. Lack of significant effect of low doses of aspirin on the concentrations of C-reactive protein in a group of individuals with atherothrombotic risk factors and vascular events. Blood Coagul Fibrinolysis 2006; 17: 19-22.
• 62 Fisher M. et al. An assessment of the joint associations of aspirin and statin use with C-reactive protein concentration. Am Heart J 2008; 156: 106-111.
• 63 Vaucher J. et al. Cytokines and hs-CRP levels in individuals treated with low-dose aspirin for cardiovascular prevention: a population-based study (CoLaus Study). Cytokine 2014; 66: 95-100.
• 64 Solheim S. et al. No difference in the effects of clopidogrel and aspirin on inflammatory markers in patients with coronary heart disease. Thromb Haemost 2006; 96: 660-664.
• 65 Ikonomidis I. et al. Cigarette smoking is associated with increased circulating proinflammatory and procoagulant markers in patients with chronic coronary artery disease: effects of aspirin treatment. Am Heart J 2005; 149: 832-839.
• 66 Gao XR. et al. Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome. J Pharm Pharmacol 2009; 61: 1505-1510.
• 67 Kronish IM. et al. Aspirin adherence, aspirin dosage, and C-reactive protein in the first 3 months after acute coronary syndrome. Am J Cardiol 2010; 106: 1090-1094.
• 68 Solheim S. et al. Influence of aspirin on inflammatory markers in patients after acute myocardial infarction. Am J Cardiol 2003; 92: 843-845.
• 69 Tousoulis D. et al. Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins. J Am Coll Cardiol 2014; 63: 2491-2502.
• 70 Owens CD. Statins and other agents for vascular inflammation. J Vasc Surg 2012; 56: 1799-1806.
• 71 Souza JR. et al. Serum levels of interleukin-6 (IL-6), interleukin-18 (IL-18) and C-reactive protein (CRP) in patients with type-2 diabetes and acute coronary syndrome without ST-segment elevation. Arq Bras Cardiol 2008; 90: 86-90.
• 72 Maier W. et al. Inflammatory markers at the site of ruptured plaque in acute myocardial infarction: locally increased interleukin-6 and serum amyloid A but decreased C-reactive protein. Circulation 2005; 111: 1355-1361.
• 73 Oemrawsingh RM. et al. Multimarker risk model containing troponin-T, inter-leukin 10, myeloperoxidase and placental growth factor predicts long-term cardiovascular risk after non-ST-segment elevation acute coronary syndrome. Heart 2011; 97: 1061-1066.
• 74 Kaptoge S. et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014; 35: 578-589.
• 75 Novo G. et al. Clinical significance of macrophage colony stimulating factor levels in acute coronary syndrome. Minerva Cardioangiol 2009; 57: 7-11.
• 76 Chen YG. et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J 2006; 119: 32-36.
• 77 Muller K. et al. Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. Atherosclerosis 2010; 213: 256-262.
• 78 Gori AM. et al. The balance between pro- and anti-inflammatory cytokines is associated with platelet aggregability in acute coronary syndrome patients. Atherosclerosis 2009; 202: 255-262.
• 79 Chiang N. et al. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev 2006; 58: 463-487.
• 80 Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res 2010; 107: 1170-1184.
• 81 Brancaleone V. et al. A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation. Blood 2013; 122: 608-617.
• 82 Chiang N. et al. Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci USA 2004; 101: 15178-15183.
• 83 FitzGerald GA. et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983; 71: 676-688.
• 84 McAdam BF. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-277.
• 85 Napoli C. et al. Nitric oxide and atherosclerosis: an update. Nitric Oxide 2006; 15: 265-279.
• 86 Taubert D. et al. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol 2004; 143: 159-165.
• 87 O’Kane PD. et al. Aspirin modifies nitric oxide synthase activity in platelets: effects of acute versus chronic aspirin treatment. Cardiovasc Res 2003; 59: 152-159.
• 88 Grosser N. et al. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun 2003; 308: 956-960.
• 89 Hetzel S. et al. Aspirin increases nitric oxide formation in chronic stable coronary disease. J Cardiovasc Pharmacol Ther 2013; 18: 217-221.
• 90 Hennekens CH. et al. A randomized trial of aspirin at clinically relevant doses and nitric oxide formation in humans. J Cardiovasc Pharmacol Ther 2010; 15: 344-348.
• 91 Magen E. et al. Effects of low-dose aspirin on blood pressure and endothelial function of treated hypertensive hypercholesterolaemic subjects. J Hum Hyper-tension 2005; 19: 667-673.
• 92 Czibik G. et al. Heme oxygenase-1: an emerging therapeutic target to curb cardiac pathology. Basic Res Cardiol 2014; 109: 450.
• 93 Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265: 956-959.
• 94 Dragomir E. et al. Aspirin and PPAR-alpha activators inhibit monocyte chemoattractant protein-1 expression induced by high glucose concentration in human endothelial cells. Vasc Pharmacol 2006; 44: 440-449.
• 95 Weber C. et al. Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation 1995; 91: 1914-1917.
• 96 Nagelschmitz J. et al. Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers. Clin Pharmacol 2014; 06: 51-59.
• 97 Yin MJ. et al. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396: 77-80.
• 98 Liu H. et al. Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice. Cardiovasc Drugs Ther 2010; 24: 17-24.
• 99 Cyrus T. et al. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 2002; 106: 1282-1287.
• 100 Saunders MA. et al. Selective suppression of CCAAT/enhancer-binding protein beta binding and cyclooxygenase-2 promoter activity by sodium salicylate in quiescent human fibroblasts. J Biol Chem 2001; 276: 18897-18904.
• 101 Mehta JL. et al. Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res 2004; 64: 243-249.
• 102 Yuan MS. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKK beta. Science 2001; 293: 1673-1677.
• 103 Wu R. et al. Antioxidative properties of acetylsalicylic acid on vascular tissues from normotensive and spontaneously hypertensive rats. Circulation 2002; 105: 387-392.
• 104 Dikshit P. et al. Aspirin induces apoptosis through the inhibition of proteasome function. J Biol Chem 2006; 281: 29228-29235.