Cytomegalovirus and Proliferative Signals in the Vascular Wall of CABG Patients

Abstract

Objective: To further elucidate the mechanism by which cytomegalovirus (CMV) may promote atherosclerosis, we studied the expression pattern of cellular inflammatory and proliferative signals in the aortic wall of CMV⁽⁺⁾ and CMV^(-) patients undergoing coronary artery bypass grafting (CABG). Methods: Aortic biopsies and blood samples of 68 CABG patients were investigated for CMV‐DNA by PCR and in situ hybridisation. Expression of pp65 antigen, adhesion molecules (ICAM-1, VCAM-1, E-selectin), growth factors (PDGF‐AA, TGF-β), and the cellular proliferation factor Ki-67 was studied by immunohistochemistry. Logistic regression was used to test the correlation between the presence of CMV, vascular inflammation, and traditional noninflammatory risk factors for atherosclerosis. Results: CMV‐DNA was detected in the aortic tissue of 52 (76 %) patients, and was localised predominantly in vascular smooth muscle cells. In CMV⁽⁺⁾ patients, the expression of adhesion molecules and growth factors in the aortic endothelium was increased compared with CMV^(-) patients. A positive correlation of elevated CRP, the induction of adhesion molecules and growth factors and CMV⁽⁺⁾ was found. Female gender, smoking, and hyperlipidaemia were identified as risk factors for CMV⁽⁺⁾. Conclusions: CMV‐DNA in smooth muscle cells induces local growth factor expression as well as endothelial activation, both of which can promote the progression of atherosclerosis. Since traditional atherogenic risk factors increase the likelihood of aortic CMV manifestation, we suggest that CMV plays a crucial role in mediating the progression of atherosclerosis.

Atherosclerosis - cytomegalovirus - adhesion molecules - growth factors

References

• 1 Libby P. What have we learned about the biology of atherosclerosis? The role of inflammation.  Am J Cardiol. 2001;  88 3-6
• 2 Degre M. Has cytomegalovirus infection any role in the development of atherosclerosis?.  Clin Microbiol Infect. 2002;  8 191-195
• 3 Horvath R, Cerny J, Benedik Jr J, Hokl J, Jelinkova I, Benedik J. The possible role of human cytomegalovirus (HCMV) in the origin of atherosclerosis.  J Clin Virol. 2000;  16 17-24
• 4 Schumacher A, Seljeflot I, Lerkerod A B, Sommervoll L, Otterstad J E, Arnesen H. Does infection with Chlamydia pneumoniae and/or Helicobacter pylori increase the expression of endothelial cell adhesion molecules in humans?.  Clin Microbiol Infect. 2002;  8 654-661
• 5 Khairy P, Rinfret S, Tardif J C. et al . Absence of association between infectious agents and endothelial function in healthy young men.  Circul. 2003;  107 1966-1971
• 6 Verschuuren E A, Harmsen M C, Limburg P C. et al . Towards standardization of the human cytomegalovirus antigenemia assay.  Intervirology. 1999;  42 382-389
• 7 Shi Y, Tokunaga O. Herpesvirus (HSV‐1, EBV and CMV) infections in atherosclerotic compared with non atherosclerotic aortic tissue.  Pathol Int. 2002;  52 31-39
• 8 Zhou Y F, Shou M, Harrell R F, Yu Z X, Unger E F, Epstein S E. Chronic non vascular cytomegalovirus infection: effects on the neointimal response to experimental vascular injury.  Cardiovasc Res. 2000;  45 1019-1025
• 9 Burnett M S, Gaydos C A, Madico G E. et al . Atherosclerosis in apoE knockout mice infected with multiple pathogens.  J Infect Dis. 2001;  183 226-231
• 10 Span A H, Frederik P M, Grauls G, Van Boven G P, Bruggeman C A. CMV induced vascular injury: an electron-microscopic study in the rat.  In Vivo. 1993;  7 567-573
• 11 Sorlie P D, Nieto F J, Adam E, Folsom A R, Shahar E, Massing M. A prospective study of cytomegalovirus, herpes simplex virus 1, and coronary heart disease: the atherosclerosis risk in communities (ARIC) study.  Arch Intern Med. 2000;  160 2027-2032
• 12 Zhou Y F, Leon M B, Waclawiw M A. et al . Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy.  N Engl J Med. 1996;  335 624-630
• 13 Hendrix M G, Salimans M M, van Boven C P, Bruggeman C A. High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis.  Am J Pathol. 1990;  136 23-28
• 14 Melnick J L, Hu C, Burek J, Adam E, DeBakey M E. Cytomegalovirus DNA in arterial walls of patients with atherosclerosis.  J Med Virol. 1994;  42 170-174
• 15 Steinhoff G, Brandt M. Adhesion molecules in liver transplantation.  Hepatogastroenterology. 1996;  43 1117-1123
• 16 Springer T A. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration.  Annu Rev Physiol. 1995;  57 827-872
• 17 Guetta E, Scarpati E M, DiCorleto P E. Effect of cytomegalovirus immediate early gene products on endothelial cell gene activity.  Cardiovasc Res. 2001;  50 538-546
• 18 Nilsson J. Cytokines and smooth muscle cells in atherosclerosis.  Cardiovasc Res. 1993;  27 1184-1190
• 19 Michelson S, Alcami J, Kim S J. et al . Human cytomegalovirus infection induces transcription and secretion of transforming growth factor beta 1.  J Virol. 1994;  68 5730-5737
• 20 Lautenschlager I, Hockerstedt K, Jalanko H. et al . Persistent cytomegalovirus in liver allografts with chronic rejection.  Hepatology. 1997;  25 190-194
• 21 Saetta A, Fanourakis G, Agapitos E, Davaris P S. Atherosclerosis of the carotid artery: absence of evidence for CMV involvement in atheroma formation.  Cardiovasc Pathol. 2000;  9 181-183
• 22 Pampou S Y, Gnedoy S N, Bystrevskaya V B. et al . Cytomegalovirus genome and the immediate-early antigen in cells of different layers of human aorta.  Virchows Arch. 2000;  436 539-552
• 23 Mendelson M, Monard S, Sissons P, Sinclair J. Detection of endogenous human cytomegalovirus in CD34+ bone marrow progenitors.  J Gen Virol. 1996;  77 3099-3102
• 24 Rauscher F M, Goldschmidt-Clermont P J, Davis B H. et al . Aging, progenitor cell exhaustion, and atherosclerosis.  Circulation. 2003;  108 457-463
• 25 Vossen R C, Derhaag J G, Slobbe-van Drunen M E, Duijvestijn A M, Dam-Mieras M C, Bruggeman C A. A dual role for endothelial cells in cytomegalovirus infection? A study of cytomegalovirus infection in a series of rat endothelial cell lines.  Virus Res. 1996;  46 65-74
• 26 Fish K N, Soderberg-Naucler C, Mills L K, Stenglein S, Nelson J A. Human cytomegalovirus persistently infects aortic endothelial cells.  J Virol. 1998;  72 5661-5668
• 27 Zhou Y F, Yu Z X, Wanishsawad C, Shou M, Epstein S E. The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF beta-receptor.  Biochem Biophys Res Commun. 1999;  256 608-613
• 28 Shahgasempour S, Woodroffe S B, Garnett H M. Alterations in the expression of ELAM‐1, ICAM‐1 and VCAM‐1 after in vitro infection of endothelial cells with a clinical isolate of human cytomegalovirus.  Microbiol Immunol. 1997;  41 121-129
• 29 Misiakos E P, Kouraklis G, Agapitos E. et al . Expression of PDGF‐A, TGFb and VCAM‐1 during the developmental stages of experimental atherosclerosis.  Eur Surg Res. 2001;  33 264-269
• 30 Cybulsky M I, Iiyama K, Li H. et al . A major role for VCAM‐1, but not ICAM‐1, in early atherosclerosis.  J Clin Invest. 2001;  107 1255-1262
• 31 Koskinen P, Lemstrom K, Bruggeman C, Lautenschlager I, Hayry P. Acute cytomegalovirus infection induces a subendothelial inflammation (endothelialitis) in the allograft vascular wall. A possible linkage with enhanced allograft arteriosclerosis.  Am J Pathol. 1994;  144 41-50
• 32 Smith P D, Saini S S, Raffeld M, Manischewitz J F, Wahl S M. Cytomegalovirus induction of tumor necrosis factor-alpha by human monocytes and mucosal macrophages.  J Clin Invest. 1992;  90 1642-1648
• 33 Iiyama K, Hajra L, Iiyama M. et al . Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation.  Circ Res. 1999;  85 199-207
• 34 Yoo Y D, Chiou C J, Choi K S. et al . The IE2 regulatory protein of human cytomegalovirus induces expression of the human transforming growth factor beta1 gene through an Egr-1 binding site.  J Virol. 1996;  70 7062-7070
• 35 Funayama H, Ikeda U, Takahashi M. et al . Human monocyte-endothelial cell interaction induces platelet-derived growth factor expression.  Cardiovasc Res. 1998;  37 216-224