The molecular basis of vulnerable plaque: Potential therapeutic role for immunomodulation

Current Opinion in Cardiology

Volumn 22, Issue 6, 2007, Pages 545-551

  Wilensky, Robert L ^a,b   Hamamdzic, Damir ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b HOSPITAL OF THE UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Lp PLA2; Oxidized LDL; PPAR agonists; Statins; T cells

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ATORVASTATIN; CIGLITAZONE; GAMMA INTERFERON; GLIBENCLAMIDE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; METFORMIN; MEVINOLIN; OXIDIZED LOW DENSITY LIPOPROTEIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PHOSPHOLIPASE A2 INHIBITOR; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE; ROSUVASTATIN; SIMVASTATIN;

ACUTE CORONARY SYNDROME; ANTIINFLAMMATORY ACTIVITY; ATHEROSCLEROSIS; ATHEROSCLEROTIC PLAQUE; BLOOD VESSEL WALL; CELL TYPE; CLINICAL TRIAL; CORRELATION ANALYSIS; DISEASE COURSE; HEART INFARCTION; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; ISCHEMIA; MACROPHAGE; MEDICAL LITERATURE; MEDICAL RESEARCH; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; RISK; T LYMPHOCYTE; TH1 CELL;

1-ALKYL-2-ACETYLGLYCEROPHOSPHOCHOLINE ESTERASE; CORONARY ARTERY DISEASE; CORONARY VESSELS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; IMMUNOLOGIC FACTORS; PPAR GAMMA;

EID: 35148852816     PISSN: 02684705     EISSN: None     Source Type: Journal    
DOI: 10.1097/HCO.0b013e3282f028fe     Document Type: Review

References (62)

1. Holvoet P, Davey PC, De Keyzer D, et al. Oxidized low-density lipoprotein correlates positively with toll-like receptor 2 and interferon regulatory factor-1 and inversely with superoxide dismutase-1 expression: studies in hypercholesterolemic swine and THP-1 cells. Arterioscler Thromb Vasc Biol 2006; 26:1558-1565. This study in an atherosclerotic large animal model showed an association between oxLDL and immune response.
2. Chang M, Binder CJ, Miller YI, et al. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J Exp Med 2004; 200: 1359-1370.
3. Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002; 91:281-291.
4. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006; 47 (Suppl 1):C13-C18.
5. Blanc-Brude OP, Teissier E, Castier Y, et al. IAP survivin regulates atherosclerotic macrophage survival. Arterioscler Thromb Vasc Biol 2007; 27:901-907. This is an initial description of survivin in human atherosclerotic plaques and demonstration of the effect and dysregulation of survivin expression.
6. Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. PNAS 2003; 100:6658-6663.
7. Robertson AL, HanssonGK. T cells in atherosclerosis: For better or for worse. Arterioscler Thromb Vasc Biol 2006; 26:2421-2432. This excellent review details the current available knowledge of the actions of T cells in the atherosclerotic plaque.
8. Andoh Y, Fujii S, Iwabuchi K, et al. Lower prevalence of circulating natural killer T cells in patients with angina: a potential novel marker for coronary artery disease. Coron Artery Dis 2006; 17:523-528.
9. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 2003; 3:984-993.
10. Shamshiev AT, Ampenberger F, Ernst B, et al. Dyslipidemia inhibits toll-like receptor-induced activation of CD8α-negative dendritic cells and protective Th1 type immunity. J Exp Med 2007; 204:441-452. This is an initial demonstration that the dyslipidemic microenvironment directly affects dendritic cell responses to pathogens resulting in impaired Th1 and enhanced Th2 responses.
11. Nissner A, Sato K, Chaikof EL, et al. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-α. Circulation 2006; 114:2482-2489. This study demonstrated a link between multiple infectious episodes and potential atherosclerotic lesion instability through plasmacytoid dendritic cell expression of IFN-α production.
12. Jeziorka M, McCollum C, Woolley DE. Mast cell distribution, activation and phenotype in atherosclerotic lesions of human carotid arteries. J Pathol 1997; 182:115-122.
13. Bot H, de Jager SCA, Zernecke A, et al. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation 2007; 115:2516-2525. This is an initial description of the potential role of mast cells in atherosclerotic plaque instability.
14. Slobedman B, Stern JL, Cunningham AL, et al. Impact of human cytomegalovirus latent infection on myeloid progenitor cell gene expression. J Virol 2004; 78:4054-4062.
15. Jenkins C, Abendroth A, Slobedman B. A novel viral transcript with homology to human interleukin-10 is expressed during latent human cytomegalovirus infection. J Virol 2004; 78:1440-1447.
16. Erkkila L, Laitinen K, Haasio K, et al. Heat shock protein 60 autoimmunity and early lipid lesions in cholesterol-fed C57BL/6JBom mice during Chlamydia pneumoniae infection. Atherosclerosis 2004; 177:321-328.
17. Hsue PY, Hunt PW, Sinclair E, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006; 20:2275-2283.
18. Clancy R, Ren Z, Pang G, et al. Chronic Chlamydia pneumoniae infection may promote coronary artery disease in humans through enhancing secretion of interleukin-4. Clin Exp Immunol 2006; 146:197-202.
19. Sawayama Y, Okada K, Maeda S, et al. Both hepatitis C virus and Chlamydia pneumoniae infection are related to the progression of carotid atherosclerosis in patients undergoing lipid lowering therapy. Fukuoka Acta Me 2006; 97:245-255.
20. Hoymans VY, Bosmans JM, Van Herck PL, et al. Implications of antibodies to heat-shock proteins in ischemic heart disease. Int J Cardiol 2007; 23 Mar [Epub ahead of print].
21. Shlitt A, Blankenberg S, Weise K, et al. Herpesvirus DNA (Epstein-Barr, herpes simplex virus, cytomegalovirus) in circulating monocytes of patients with coronary artery disease. Acta Cardiologica 2005; 60: 605-610.
22. Guech-Ongey M, Bremer H, Twardella D, et al. Role of cytomegalovirus serostatus in the development of secondary cardiovascular events in patients with coronary artery disease under special consideration of diabetes. Int J Cardiol 2006; 111:98-103.
23. Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005; 352:1646-1654.
24. Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques. Circulation 2001; 103:926-933.
25. Solem J, Levin M, Karlsson T, et al. Composition of coronary plaques obtained by directional atheroectomy in stable angina: its relation to serum lipids and statin treatment. J Int Med 2006; 259:267-275.
26. Jury EC, Isenberg DA, Mauri C, Ehrenstein MR. Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol 2006; 177:7416-7422. This study demonstrated the mechanism by which atorvastatin effects T-cell activation.
27. Ghittoni R, Lazzerini RE, Paini FL, Baldari CT. T lymphocytes as targets of statins: Molecular mechanism and therapeutic perspectives. Inflamm Allergy Drug Targets 2007; 6:3-16.
28. Veillard NR, Braunersreuther V, Arnaud C, et al. Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages. Atherosclerosis 2006; 188:51-58. This study elucidated a potential mode of action of statins via isoprenylation.
29. Ghittoni R, Napolitani G, Benati D, et al. Simvastatin inhibits the MHC class II pathway of antigen presentation by impairing Ras superfamily GTPases. Eur J Immunol 2006; 36:2885-2893. The authors present a description of a potential mode of action of simvastatin on presentation of antigens by dendritic cells to T-cells by effecting prenylation in the absence of an effect on lipid rafts.
30. Link A, Ayadhi T, Böhm M, Nickenig G. Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. Eur Heart J 2006; 27: 2945-2955. This clinical study showed the rapid anti-inflammatory and immunomodulatory effects of a statin during an acute coronary syndrome episode and lends insight into the early pleiotropic effects of statins.
31. Weitz-Schmidt G, Welzenbach K, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001; 7:687-692.
32. van Seventer GA, Semani RT, Plamer EM, et al. Integrins and T helper cell activation. Transplant Proc 1998; 30:4270-4274.
33. Arora M, Chen L, Paglia M, Gallagher I, et al. Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells. PNAS 2006; 103:7777-7782. This study demonstrated the potential mode of action of simvastatin in antiatherogenic Th2 response.
34. Coward W, Chow SC. Effect of atorvastatin on Th1 and Th2 cytokine secreting cells during T cell activation and differentiation. Atherosclerosis 2006; 186:302-309.
35. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6:1399-1402.
36. Mulhaupt F, Matter CM, Kwak BR. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells. Cardiovasc Res 2003; 59:755-766.
37. 2 on markers of vascular inflammation.
38. 2 and unstable coronary plaques.
39. O'Donoghue M, Morrow DA, Sabatine MS, et al. Lipoprotein associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thombolysis in Myocardial Infarction) trial. Circulation 2006; 113:1745-1752. This clinical study showed that increased Lp-PLA2 activity was associated with cardiovascular events over 30 days after initial presentation for an acute coronary syndrome. The results would suggest that Lp-PLA2 is a marker of disease progression rather than acute instability.
40. 2 and prognosis after myocardial infarction in the community. Arterioscl Thromb Vasc Biol 2006; 26:2517-2522.
41. Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscl Thromb Vasc Biol 2006; 26:1586-1593.
42. May HT, Horne BD, Anderson JL, et al. Lipoprotein associated phospholipase A2 independently predicts the angiographic diagnosis of coronary artery disease and coronary death. Am Heart J 2006; 152:997-1003.
43. Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 2006; 6:47-55.
44. VanBuskirk AM, Lesinski GB, Nye KJ, et al. TGF-b inhibition of CTL re-stimulation requires accessory cells and induces peroxisome-proliferator- activated-receptor-gamma (PPAR-g). Am J Transpl 2006; 6:1809-1819.
45. Alleva DG, Johnson EB, Lio FM, et al. Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-gamma: Counter-regulatory activity by IFN-gamma. J Leukoc Biol 2002; 71:677-685.
46. Blaschke F, Spanheimer R, Khan M, Law RE. Vascular effects of TZDs: New implications. Vasc Pharm 2006; 45:3-18.
47. Coutant F, Agaugué S, Perrin-Cocon L, et al. Sensing environmental lipids by dendritic cell modulates its function. J Immunol 2004; 172: 54-60.
48. Saubermann LJ, Natajima A, Wada K, et al. Peroxisome proliferator-activated receptor γ agonist ligands stimulate a Th2 cytokine response and prevent acute colitis. Inflamm Bowel Dis 2002; 8:330-339.
49. 2. J Neuroimmunol 2006; 178:76-86. This study confirmed a physiological role for PPAR-γ in regulation of CNS inflammation and demyelination in experimental allergic encephalomyelitis.
50. Hasegawa H, Takano H, Zou Y, et al. Pioglitazone, a peroxisome proliferator-activated receptor gamma activator, ameliorates experimental autoimmune myocarditis by modulating Th1/Th2 balance. J Mol Cell Cardiol 2005; 38: 257-265.
51. Blaschke F, Caglayan E, Hsueh WA. Peroxisome proliferator-activated receptor gamma agonist: Their role as vasculoprotective agents in diabetes. Endocrinol Metab Clin N Am 2006; 35:561-574.
52. Joner M, Farb A, Cheng Q, et al. Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-β and MCP-1. Arterioscler Thromb Vasc Biol 2007; 27:182-189. This study defined the potential mechanism by which pioglitazone inhibits macrophage accumulation and restenosis after stent implantation.
53. Kosuge H, Haraguchi G, Koga N, et al. Pioglitazone prevents acute and chronic cardiac allograft rejection. Circulation 2006; 113:2613-2622. The study showed the immunomodulatory effects of pioglitazone in a cardiac transplantation model and demonstrated significant reduction in posttransplant coronary artery disease.
54. Stocker DJ, Taylor AJ, Langley RW, et al. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J 2007; 153:445.e1-445.e6.
55. Hedblad B, Zambanini A, Nilsson P, et al. Rosiglitazone and carotid IMT progression rate in a mixed cohort of patients with type 2 diabetes and the insulin resistance syndrome: main results from the rosiglitazone atherosclerosis study. J Intern Med 2007; 261:293-305.
56. Marfella R, D'Amico M, Esposito K, et al. The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques. Diabetes 2006; 55:622-632. This clinical study showed an association between the ubiquitin-protease system and carotid artery inflammation and the pathoanatomic effects of rosiglitazone with stabilization of lesions.
57. Herrmann J, Ciechanover A, Lerman LO, Lerman A. The ubiquitin-protease system in cardiovascular diseases: a hypothesis extended. Cardiovasc Res 2004; 61:11-21.
58. Dormany JA, Charbonnel B, Eckland A, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomized controlled trial. Lancet 2005; 366:1279-1289.
59. Erdmann E, Dormandy JA, Charbonnel B, et al. PROactive substudy: Less frequent reinfarction and ACS with pioglitazone for patients with T2DM and previous MI. J Am Coll Cardiol 2007; 49:1772-1780. Post-hoc analysis of the PROactive study demonstrated an effect of pioglitazone in reducing coronary instability.
60. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. N Engl J Med 2006; 355:2427-2443. Although designed to evaluate long-term glycemic control using three antidiabetic medications, the results show a potential signal of the long-term effects of rosiglitazone on incidence of myocardial infarction.
61. Dream Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006; 368:1096-1105. As with the ADOPT trial the DREAM study raises the question of whether the effects of PPARγ agonism represent a class effect or whether there are potential differences with regard to cardiovascular events.
62. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457-2471.