Advertisement

Role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, angiotensin-converting enzyme inhibitors, cyclooxygenase-2 inhibitors, and aspirin in anti-inflammatory and immunomodulatory treatment of cardiovascular diseases

      Abstract

      The immunologic response in atherosclerosis involves not only intrinsic cells of the artery wall, but also circulating leukocytes, lymphocytes, and macrophages. Interaction of various arms of the immune response modulates plaque development and stability, and it is conceivable that immunologic effects of some cardiovascular therapies may contribute to their mechanism of benefit. The preponderance of data has accrued with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Statin effects, such as inhibition of T cell activation, tissue factor expression, or reduction of platelet hyperreactivity, may elicit beneficial effects in vitro and in vivo in patients with coronary artery disease. Moreover, aspirin may limit oxidation of lipoproteins and fibrinogen, and it may inhibit cytokine-induced nitric oxide synthase II expression. The hypothesis that selective inhibition of cyclooxygenase-2 (COX-2) may increase risk of myocardial infarction is controversial and may also be of questionable clinical significance. Finally, angiotensin-converting enzyme (ACE) inhibitors not only reduce proinflammatory mediators, such as interleukin-6, but also enhance the concentration of anti-inflammatory cytokines, such as interleukin-10. Because ACE is expressed at the shoulder region of atherosclerotic plaques, and ACE activity is enhanced in unstable plaques, ACE inhibition may also contribute to plaque stability. This article reviews the potential immunomodulatory potencies of aspirin, COX-2 inhibitors, statins, and ACE inhibitors as established pharmacotherapy in patients with coronary artery disease.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Stone E. An account of the success of the bark of the willow tree in the cure of agues. Philos Trans R Soc Lond 1763;53:195–200

        • Dreser H.
        Pharmakologisches über aspirin (acetylsalicylsäure).
        Pflugers Arch. 1899; 76: 306-318
        • Vane J.R.
        Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.
        Nat New Biol. 1971; 231: 232-235
        • Fuster V.
        • Dyken M.L.
        • Vokonas P.S.
        • Hennekens C.
        Aspirin as a therapeutic agent in cardiovascular disease.
        Circulation. 1993; 87: 659-675
        • Smith W.L.
        Prostanoid biosynthesis and mechanisms of action.
        Am J Physiol. 1992; 263: F181-F191
        • Williams C.S.
        • DuBois R.N.
        Prostaglandin endoperoxide synthase.
        Am J Physiol. 1996; 270: G393-G400
        • Gierse J.K.
        • McDonald J.J.
        • Hauser S.D.
        • Rangwala S.H.
        • Koboldt C.M.
        • Seibert K.
        A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors.
        J Biol Chem. 1996; 271: 15810-15814
        • Hawkey C.J.
        COX-2 inhibitors.
        Lancet. 1999; 353: 307-314
        • Morita I.
        • Schindler M.
        • Regier M.K.
        • Otto J.C.
        • Hori T.
        • DeWitt D.L.
        • Smith W.L.
        Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2.
        J Biol Chem. 1995; 270: 10902-10908
        • Roth G.J.
        • Majerus P.W.
        The mechanism of the effect of aspirin on human platelets, I.
        J Clin Invest. 1975; 56: 624-632
        • Loll P.J.
        • Picot D.
        • Garavito R.M.
        The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.
        Nat Struct Biol. 1995; 2: 637-643
        • Vane J.R.
        • Bakhle Y.S.
        • Botting R.M.
        Cyclooxygenases 1 and 2.
        Annu Rev Pharmacol Toxicol. 1998; 38: 97-120
        • FitzGerald G.A.
        Mechanisms of platelet activation.
        Am J Cardiol. 1991; 68: 11B-15B
        • Steer K.A.
        • Wallace T.M.
        • Bolton C.H.
        • Hartog M.
        Aspirin protects low density lipoprotein from oxidative modification.
        Heart. 1997; 77: 333-337
        • Lopez-Farre A.
        • Caramelo C.
        • Esteban A.
        • Alberola M.L.
        • Millas I.
        • Monton M.
        • Casado S.
        Effects of aspirin on platelet-neutrophil interactions.
        Circulation. 1995; 91: 2080-2088
        • Bolz S.S.
        • Pohl U.
        Indomethacin enhances endothelial NO release.
        Cardiovasc Res. 1997; 36: 437-444
        • Husain S.
        • Andrews N.P.
        • Mulcahy D.
        • Panza J.A.
        • Quyyumi A.A.
        Aspirin improves endothelial dysfunction in atherosclerosis.
        Circulation. 1998; 97: 716-720
        • Farivar R.S.
        • Brecher P.
        Salicylate is a transcriptional inhibitor of the inducible nitric oxide synthase in cultured cardiac fibroblasts.
        J Biol Chem. 1996; 271: 31585-31592
        • Kimura A.
        • Roseto J.
        • Suh K.Y.
        • Cohen A.M.
        • Bing R.J.
        Effect of acetylsalicylic acid on nitric oxide production in infarcted heart in situ.
        Biochem Biophys Res Commun. 1998; 251: 874-878
        • Ghiselli A.
        • Laurenti O.
        • De Mattia G.
        • Maiani G.
        • Ferro-Luzzi A.
        Salicylate hydroxylation as an early marker of in vivo oxidative stress in diabetic patients.
        Free Radic Biol Med. 1992; 13: 621-626
        • Betts W.H.
        • Whitehouse M.W.
        • Clelend L.G.
        • Vernon-Roberts B.
        In vitro antioxidant properties of potential biotransformation products of salicylate, sulfasalazine and aminopyrine.
        J Free Radic Biol Med. 1985; 1: 273-280
        • Pinckard R.N.
        • Hawkins D.
        • Farr R.S.
        In vitro acetylation of plasma proteins, enzymes and DNA by aspirin.
        Nature. 1968; 219: 68-69
        • Ezratty A.
        • Freedman J.E.
        • Simon D.
        • Loscalzo J.
        The antithrombotic effects of acetylation of fibrinogen by aspirin.
        J Vasc Med Biol. 1994; 5: 152-159
        • Bjornsson T.D.
        • Schneider D.E.
        • Berger Jr, H.
        Aspirin acetylates fibrinogen and enhances fibrinolysis.
        J Pharmacol Exp Ther. 1989; 250: 154-161
        • Ridker P.M.
        • Cushman M.
        • Stampfer M.J.
        • Tracey R.P.
        • Hennekens C.H.
        Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
        N Engl J Med. 1997; 336: 973-979
        • Peto R.
        • Gray R.
        • Collins R.
        • Wheatley K.
        • Hennekens C.
        • Jamrozik K.
        • Warlow C.
        • Hafner B.
        • Thompson E.
        • Norton S.
        • Gilliland J.
        • Doll R.
        Randomised trial of prophylactic daily aspirin in British male doctors.
        BMJ. 1988; 296: 313-316
        • Antiplatelet Trialists’ Collaboration
        Collaborative overview of randomised trials of antiplatelet therapy. I.
        BMJ. 1994; 308: 81-106
        • Hennekens C.H.
        • Peto R.
        • Hutchison G.B.
        • Doll R.
        An overview of the British and American aspirin studies.
        N Engl J Med. 1988; 318: 923-924
        • FitzGerald G.A.
        • Oates J.A.
        • Hawiger J.
        • Maas R.L.
        • Roberts II, L.J.
        • Lawson J.A.
        • Brash A.R.
        Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.
        J Clin Invest. 1983; 71: 676-688
        • Penderson A.K.
        • FitzGerald G.A.
        Dose-related kinetics of aspirin.
        N Engl J Med. 1984; 311: 1206-1211
        • Patrono C.
        • Ciabattoni G.
        • Patrignani P.
        • Pugliese F.
        • Filabozzi P.
        • Catella F.
        • Davi G.
        • Forni L.
        Clinical pharmacology of platelet cyclooxygenase inhibition.
        Circulation. 1985; 72: 1177-1184
        • Engelhardt G.
        • Homma D.
        • Schlegel K.
        • Utzmann R.
        • Schnitzler C.
        Anti-inflammatory, analgesic, anti-pyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favorable gastrointestinal tolerance.
        Inflamm Res. 1995; 44: 423-433
        • Aspirin Myocardial Infarction Study Research Group
        The Aspirin Myocardial Infarction Study.
        Circulation. 1980; 62: V-79-V-84
        • Coronary Drug Project Research Group
        Aspirin in coronary heart disease.
        J Chronic Dis. 1976; 29: 625-642
        • Altman R.
        • Luciardi H.L.
        • Muntaner J.
        • Del Rio F.
        • Berman S.G.
        • Lopez R.
        • Gonzalez C.
        Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation.
        Circulation. 2002; 106: 191-195
        • Goldstein J.L.
        • Brown M.S.
        Regulation of the mevalonate pathway.
        Nature. 1990; 343: 425-430
        • Massy Z.A.
        • Keane W.F.
        • Kasiske B.L.
        Inhibition of the mevalonate pathway.
        Lancet. 1996; 347: 102-103
        • Dangas G.
        • Smith D.A.
        • Unger A.H.
        • Shao J.H.
        • Meraj P.
        • Fier C.
        • Cohen A.M.
        • Fallon J.T.
        • Badimon J.J.
        • Ambrosea J.A.
        Pravastatin.
        Thromb Haemost. 2000; 83: 688-692
        • Guijarro C.
        • Blanco-Colio L.M.
        • Ortego M.
        • Alonso C.
        • Ortiz A.
        • Plaza J.J.
        • Diaz C.
        • Hernandez G.
        • Egido J.
        3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture.
        Circ Res. 1998; 83: 490-500
        • LaRosa J.C.
        • He J.
        • Vupputuri S.
        Effect of statins on risk of coronary disease.
        JAMA. 1999; 282: 2340-2346
        • Kwak B.
        • Mulhaupt F.
        • Myit S.
        • Mach F.
        Statins as a newly recognized type of immunomodulator.
        Nat Med. 2000; 6: 1399-1402
        • Lacoste L.
        • Lam J.Y.
        • Hung J.
        • Letchacovski G.
        • Solymoss C.B.
        • Waters D.
        Hyperlipidemia and coronary disease.
        Circulation. 1995; 92: 3172-3177
        • Notarbartolo A.
        • Davi G.
        • Averna M.
        • Barbagallo C.M.
        • Ganci A.
        • Giammarresi C.
        • La Placa F.P.
        • Patrono C.
        Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia.
        Arterioscler Thromb Vasc Biol. 1995; 15: 247-251
        • Leung W.H.
        • Lau C.P.
        • Wong C.K.
        Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients.
        Lancet. 1993; 341: 1496-1500
        • Ortego M.
        • Bustos C.
        • Hernandez-Presa M.A.
        • Tunon J.
        • Diaz C.
        • Hernandez G.
        • Egido J.
        Atorvastatin reduces NF-κB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells.
        Atherosclerosis. 1999; 147: 253-261
        • Feron O.
        • Dessy C.
        • Desager J.-P.
        • Balligand J.-L.
        Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance.
        Circulation. 2001; 103: 113-118
        • Laufs U.
        • Gertz K.
        • Huang P.
        • Nickenig G.
        • Bohm M.
        • Dirnagl U.
        • Endres M.
        Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice.
        Stroke. 2000; 31: 2442-2449
        • Essig M.
        • Vrtovsnik F.
        • Nguyen G.
        • Sraer J.D.
        • Friedlander G.
        Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells.
        J Am Soc Nephrol. 1998; 9: 1377-1388
        • Ridker P.M.
        • Rifai N.
        • Pfeffer M.A.
        • Sacks F.
        • Braunwald E.
        • The Cholesterol and Recurrent Events (CARE) Investigators
        Long-term effects of pravastatin on plasma concentration of C-reactive protein.
        Circulation. 1999; 100: 230-235
        • Kinlay S.
        • Selwyn A.P.
        Effects of statins on inflammation in patients with acute and chronic coronary syndromes.
        Am J Cardiol. 2003; 91: 9B-13B
        • Kobashigawa J.A.
        • Katznelson S.
        • Laks H.
        • Johnson J.A.
        • Yeatman L.
        • Wang X.M.
        • Chia D.
        • Terasaki P.I.
        • Sabad A.
        • Cogert G.A.
        • et al.
        Effect of pravastatin on outcomes after cardiac transplantation.
        N Engl J Med. 1995; 333: 621-627
        • Wenke K.
        • Meiser B.
        • Thiery J.
        • Nagel D.
        • von Scheidt W.
        • Steinbeck G.
        • Seidel D.
        • Reichart B.
        Simvastatin reduces graft vessel disease and mortality after heart transplantation.
        Circulation. 1997; 96: 1398-1402
        • Ross R.
        Atherosclerosis.
        N Engl J Med. 1999; 340: 115-126
        • Fuster V.
        • Fayad Z.A.
        • Badimon J.J.
        Acute coronary syndromes.
        Lancet. 1999; 353: SII5-SII9
        • Dzau V.J.
        Theodore Cooper Lecture.
        Hypertension. 2001; 37: 1047-1052
        • Jackson E.K.
        Renin and angiotensin.
        in: Hardman J.G. Limbird L.E. Gilman A.G. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. McGraw-Hill, New York2001
        • Dzau V.J.
        • Bernstein K.
        • Celermajer D.
        • Cohen J.
        • Dahlof B.
        • Deanfield J.
        • Diez J.
        • Drexler H.
        • Ferrari R.
        • Van Gilst W.
        • et al.
        The relevance of tissue angiotensin-converting enzyme.
        Am J Cardiol. 2001; 88: 1L-20L
        • Tallant E.A.
        • Diz D.I.
        • Ferrario C.M.
        Antiproliferative actions of angiotensin (1-7) in vascular smooth muscle.
        Hypertension. 1999; 34: 950-957
        • Linz W.
        • Wohlfart P.
        • Schoelkens B.A.
        • Malinski T.
        • Wiemer G.
        Interactions among ACE, kinins and NO.
        Cardiovasc Res. 1999; 43: 549-561
        • Maassen van den Brink A.
        • de Vries R.
        • Danser A.H.
        ACE, but not chymase, generates angiotensin II in close proximity to the AT1-receptor in human isolated coronary arteries.
        Circulation. 1998; 98: I-606
        • Blume A.
        • Kaschina E.
        • Unger T.
        Angiotensin II type 2 receptors.
        Curr Opin Nephrol Hypertens. 2001; 10: 239-246
        • Kerins D.M.
        • Hao Q.
        • Vaughan D.E.
        Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV.
        J Clin Invest. 1995; 96: 2515-2520
        • Griendling K.K.
        • Minieri C.A.
        • Ollerenshaw J.D.
        • Alexander R.W.
        Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.
        Circ Res. 1994; 74: 1141-1148
        • Schieffer B.
        • Luchtefeld M.
        • Braun S.
        • Hilfiker A.
        • Hilfiker-Kleiner D.
        • Drexler H.
        Role of NAD(P)H oxidase in angiotensin II-induced JAK/STAT signaling and cytokine induction.
        Circ Res. 2000; 87: 1195-1201
        • Kranzhöfer R.
        • Schmidt J.
        • Pfeiffer C.A.H.
        • Hagl S.
        • Libby P.
        • Kübler W.
        Angiotensin induces inflammatory activation of human vascular smooth muscle cells.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1623-1629
        • Schieffer B.
        • Schieffer E.
        • Hilfiker-Kleiner D.
        • Hilfiker A.
        • Kovanen P.T.
        • Kaartinen M.
        • Nussberger J.
        • Harringer W.
        • Drexler H.
        Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques.
        Circulation. 2000; 101: 1372-1378
        • Diet F.
        • Pratt R.E.
        • Berry G.J.
        • Momose N.
        • Gibbons G.H.
        • Dzau V.J.
        Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease.
        Circulation. 1996; 94: 2756-2767
        • Hoshida S.
        • Kato J.
        • Nishino M.
        • Egami Y.
        • Takeda T.
        • Kawabata M.
        • Tanouchi J.
        • Yamada Y.
        • Kamada T.
        Increased angiotensin-converting enzyme activity in coronary artery specimens from patients with acute coronary syndrome.
        Circulation. 2001; 103: 630-633
        • Potter D.D.
        • Sobey C.G.
        • Tompkins P.K.
        • Rossen J.D.
        • Heistad D.D.
        Evidence that macrophages in atherosclerotic lesions contain angiotensin II.
        Circulation. 1998; 98: 800-807
        • Moreno P.R.
        • Falk E.
        • Palaicos I.F.
        • Newell J.B.
        • Fuster V.
        • Fallon J.T.
        Macrophage infiltration in acute coronary syndromes implications for plaque rupture.
        Circulation. 1994; 90: 775-778
        • Kossakowska A.E.
        • Edwards D.R.
        • Prusinkiewicz C.
        • Zhang M.C.
        • Guo D.
        • Urbanski S.J.
        • Grogan T.
        • Marquez L.A.
        • Janowska-Wieczorek A.
        Interleukin-6 regulation of matrix metalloproteinase (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin’s lymphomas.
        Blood. 1999; 94: 2080-2089
        • Rutherford J.D.
        • Pfeffer M.A.
        • Moye L.A.
        • Davis B.R.
        • Flaker G.C.
        • Kowey P.R.
        • Lamas G.A.
        • Miller H.S.
        • Packer M.
        • Pouleau J.L.
        • et al.
        Effects of captopril on ischemic events after myocardial infarction.
        Results of the Survival and Ventricular Enlargement trial. SAVE Investigators. Circulation. 1994; 90: 1731-1738
        • Kober L.
        • Torp-Pedersen C.
        • Carlsen J.E.
        • Bagger H.
        • Eliasen P.
        • Lynborg K.
        • Videbaek J.
        • Cole D.S.
        • Auclert L.
        • Pauly N.C.
        A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.
        N Engl J Med. 1995; 333: 1670-1676
        • SOLVD Investigators
        Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction.
        N Engl J Med. 1992; 327: 685-691
        • Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
        Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
        Lancet. 1993; 342: 821-828
        • Flather M.D.
        • Yusuf S.
        • Kober L.
        • Pfeffer M.
        • Hall A.
        • Murray G.
        • Torp-Pedersen C.
        • Ball S.
        • Pogue J.
        • Moye L.
        • Braunwald E.
        Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction.
        Lancet. 2000; 355: 1575-1581
        • Heart Outcomes Prevention Evaluation Study Investigators
        Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
        N Engl J Med. 2000; 342: 145-153
        • Biassuci L.
        • Vitelli A.
        • Liuzzo G.
        • Altamura S.
        • Caliguri G.
        • Monaco C.
        • Rebuzzi A.
        • Ciliberto G.
        • Maseri A.
        Elevated levels of interleukin-6 in unstable angina.
        Circulation. 1996; 94: 874-877
        • Bünte C.
        • Witte J.
        • Hoeper K.
        • Schieffer B.
        Contrasting anti-atherosclerotic effects of AT1-antagonism and ACE inhibition in patients with coronary artery disease.
        Circulation. 2002; 19 (Abstract 1684): II-337
        • Chobanian A.V.
        • Haudenschild C.C.
        • Nickerson C.
        • Drago R.
        Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit.
        Hypertension. 1990; 15: 327-331
        • Powell J.S.
        • Clozel J.P.
        • Muller R.K.
        • Kuhn H.
        • Hefti F.
        • Hosang M.
        • Baumgartner H.R.
        Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury.
        Science. 1989; 245: 186-188
        • Chobanian A.V.
        • Haudenschild C.C.
        • Nickerson C.
        • Hope S.
        Trandolapril inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits.
        Hypertension. 1992; 20: 473-477