High prevalence of human cytomegalovirus in carotid atherosclerotic plaques obtained from Russian patients undergoing carotid endarterectomy
Tóm tắt
Human cytomegalovirus (HCMV) infection is associated with cardiovascular disease (CVD) but the role of this virus in CVD progression remains unclear. We aimed to examine the HCMV serostatus in Russian patients (n = 90) who had undergone carotid endarterectomy (CEA) and controls (n = 82) as well as to determine the prevalence of HCMV immediate early (IE) and late (LA) antigens in carotid atherosclerotic plaques obtained from 89 patients. In addition, we sought to determine whether HCMV infection was associated with inflammatory activity in the plaque by quantifying infiltrating CD3 and CD68 positive cells and 5-LO immunoreactivity. HCMV serology was assessed with ELISA and immunohistochemistry staining was performed to detect HCMV antigens, CD3, CD68 and 5-LO reactivity. The Fisher’s exact test was used to compare i) seroprevalence of HCMV IgG between patients and controls and ii) HCMV-positive or –negative to that of CD3, CD68 and 5-LO immunoreactive cells in plaque samples. The student-t test was performed to connote the significance level of mean optical density between patients and controls. The seroprevalence for HCMV IgG was high in both patients and controls (99% and 98%, respectively). Controls had significantly higher IgG titers for HCMV compared with patients (p = 0.0148). Strikingly, we found a high prevalence of HCMV antigens in atherosclerotic plaques; 57/89 (64%) and 47/87 (54%) were HCMV IE and LA positive, respectively. Most plaques had rather low HCMV reactivity with distinct areas of HCMV-positive cells mainly detected in shoulder regions of the plaques, but also in the area adjacent to the necrotic core and fibrous cap. In plaques, the cellular targets for HCMV infection appeared to be mainly macrophages/foam cells and smooth muscle cells. HCMV-positive plaques trended to be associated with increased numbers of CD68 positive macrophages and CD3 positive T cells, while 5-LO reactivity was high in both HCMV-positive and HCMV-negative plaques. In Russian patients undergoing CEA, HCMV proteins are abundantly expressed in carotid plaques and may contribute to the inflammatory response in plaques via enhanced infiltration of CD68 and CD3 cells.
Tài liệu tham khảo
Mocarski ES, Courcelle CT: Cytomegaloviruses and their replication. Fields Virology, Volume 2. Edited by: Knipe D, Howley PM. 2001, Philadelphia: Lippincott Williams and Wilkins, 2629-2673. 4
Cannon MJ, Schmid DS, Hyde TB: Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010, 20 (4): 202-213.
Rosenfeld ME, Campbell LA: Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost. 2011, 106 (5): 858-867.
Epstein SE, Zhou YF, Zhu J: Infection and atherosclerosis: emerging mechanistic paradigms. Circulation. 1999, 100 (4): e20-e28.
Simanek AM, Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE: Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS One. 2011, 6 (2): e16103-
Joshi R, Khandelwal B, Joshi D, Gupta OP: Chlamydophila pneumoniae infection and cardiovascular disease. N Am J Med Sci. 2013, 5 (3): 169-181.
Charakida M, Tousoulis D: Infections and atheromatous plaque: current therapeutic implications. Curr Pharm Des. 2013, 19 (9): 1638-1650.
Streblow DN, Orloff SL, Nelson JA: Do pathogens accelerate atherosclerosis?. J Nutr. 2001, 131 (10): 2798s-2804s.
Popovic M, Smiljanic K, Dobutovic B, Syrovets T, Simmet T, Isenovic ER: Human cytomegalovirus infection and atherothrombosis. J Thromb Thrombolysis. 2012, 33 (2): 160-172.
Melnick JL, Petrie BL, Dreesman GR, Burek J, McCollum CH, DeBakey ME: Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet. 1983, 2 (8351): 644-647.
Hendrix MG, Salimans MM, van Boven CP, Bruggeman CA: High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol. 1990, 136 (1): 23-28.
Blum A, Peleg A, Weinberg M: Anti-cytomegalovirus (CMV) IgG antibody titer in patients with risk factors to atherosclerosis. Clin Exp Med. 2003, 3 (3): 157-160.
Blum A, Giladi M, Weinberg M, Kaplan G, Pasternack H, Laniado S, Miller H: High anti-cytomegalovirus (CMV) IgG antibody titer is associated with coronary artery disease and may predict post-coronary balloon angioplasty restenosis. Am J Cardiol. 1998, 81 (7): 866-868.
Roberts ET, Haan MN, Dowd JB, Aiello AE: Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am J Epidemiol. 2010, 172 (4): 363-371.
Strandberg TE, Pitkala KH, Tilvis RS: Cytomegalovirus antibody level and mortality among community-dwelling older adults with stable cardiovascular disease. Jama-J Am Med Assoc. 2009, 301 (4): 380-382.
Wang GC, Kao WH, Murakami P, Xue QL, Chiou RB, Detrick B, McDyer JF, Semba RD, Casolaro V, Walston JD, et al: Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol. 2010, 171 (10): 1144-1152.
Cheng J, Ke Q, Jin Z, Wang H, Kocher O, Morgan JP, Zhang J, Crumpacker CS: Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog. 2009, 5 (5): e1000427-
Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, Ma X, Lau WB, Rong R, Yu X, et al: Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. Circulation. 2011, 124 (2): 175-184.
Cour MI, Deatalaya FJL, Palau L, Contreras EF, Perezagua C: Lack of serological association between herpesvirus and atherosclerosis. Lancet. 1989, 1 (8632): 279-279.
Borgia MC, Mandolini C, Barresi C, Battisti G, Carletti F, Capobianchi MR: Further evidence against the implication of active cytomegalovirus infection in vascular atherosclerotic diseases. Atherosclerosis. 2001, 157 (2): 457-462.
Libby P: Inflammation in atherosclerosis. Nature. 2002, 420 (6917): 868-874.
Hansson GK, Robertson AK, Soderberg-Naucler C: Inflammation and atherosclerosis. Annu Rev Pathol. 2006, 1: 297-329.
Jawien J, Korbut R: The current view on the role of leukotrienes in atherogenesis. J Physiol Pharmacol. 2010, 61 (6): 647-650.
Radmark O, Samuelsson B: 5-lipoxygenase: regulation and possible involvement in atherosclerosis. Prostaglandins Other Lipid Mediat. 2007, 83 (3): 162-174.
Qiu H, Straat K, Rahbar A, Wan M, Soderberg-Naucler C, Haeggstrom JZ: Human CMV infection induces 5-lipoxygenase expression and leukotriene B4 production in vascular smooth muscle cells. J Exp Med. 2008, 205 (1): 19-24.
Soderberg-Naucler C, Fish KN, Nelson JA: Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997, 91 (1): 119-126.
Reeves MB, MacAry PA, Lehner PJ, Sissons JG, Sinclair JH: Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci U S A. 2005, 102 (11): 4140-4145.
Soderberg-Naucler C, Fish KN, Nelson JA: Interferon-gamma and tumor necrosis factor-alpha specifically induce formation of cytomegalovirus-permissive monocyte-derived macrophages that are refractory to the antiviral activity of these cytokines. J Clin Invest. 1997, 100 (12): 3154-3163.
Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, Khan Z, Sveinbjornsson B, FuskevAg OM, Segerstrom L, et al: Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011, 121 (10): 4043-4055.
Dzabic M, Rahbar A, Yaiw KC, Naghibi M, Religa P, Fellstrom B, Larsson E, Soderberg-Naucler C: Intragraft cytomegalovirus protein expression is associated with reduced renal allograft survival. Clin Infect Dis. 2011, 53 (10): 969-976.
Soderberg-Naucler C: Human cytomegalovirus persists in its host and attacks and avoids elimination by the immune system. Crit Rev Immunol. 2006, 26 (3): 231-264.
Maussang D, Langemeijer E, Fitzsimons CP, Stigter-van Walsum M, Dijkman R, Borg MK, Slinger E, Schreiber A, Michel D, Tensen CP, et al: The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res. 2009, 69 (7): 2861-2869.
Varani S, Rossini G, Mastroianni A, Tammik C, Frascaroli G, Landini MP, Castellani G, Soderberg-Naucler C: High TNF-alpha and IL-8 levels predict low blood dendritic cell counts in primary cytomegalovirus infection. J Clin Virol. 2012, 53 (4): 360-363.
Carlquist JF, Edelman L, Bennion DW, Anderson JL: Cytomegalovirus induction of interleukin-6 in lung fibroblasts occurs independently of active infection and involves a G protein and the transcription factor. NF-kappaB. J Infect Dis. 1999, 179 (5): 1094-1100.
Luc G, Bard JM, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P, Arveiler D, Fruchart JC, Ducimetiere P, Grp PS: C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease - The PRIME study. Arterioscl Throm Vas. 2003, 23 (7): 1255-1261.
Chen RZ, Xiong SD, Yang YZ, Fu WG, Wang YQ, Ge JB: The relationship between human cytomegalovirus infection and atherosclerosis development. Mol Cell Biochem. 2003, 249 (1–2): 91-96.
Chiu B, Viira E, Tucker W, Fong IW: Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus in atherosclerosis of the carotid artery. Circulation. 1997, 96 (7): 2144-2148.
Yi L, Wang DX, Feng ZJ: Detection of human cytomegalovirus in atherosclerotic carotid arteries in humans. J Formos Med Assoc. 2008, 107 (10): 774-781.
Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R: Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol. 2008, 116 (1): 79-86.
Inzitari D, Hachinski VC, Taylor DW, Barnett HJ: Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors?. Arch Neurol. 1990, 47 (10): 1080-1084.
Hagiwara N, Toyoda K, Inoue T, Shimada H, Ibayashi S, Iida M, Okada Y: Lack of association between infectious burden and carotid atherosclerosis in Japanese patients. J Stroke Cerebrovasc Dis. 2007, 16 (4): 145-152.
Soderberg-Naucler C: HCMV microinfections in inflammatory diseases and cancer. J Clin Virol. 2008, 41 (3): 218-223.
Powers C, DeFilippis V, Malouli D, Fruh K: Cytomegalovirus immune evasion. Curr Top Microbiol Immunol. 2008, 325: 333-359.
Stollberger C, Finsterer J: Role of infectious and immune factors in coronary and cerebrovascular arteriosclerosis. Clin Diagn Lab Immunol. 2002, 9 (2): 207-215.
Cipollone F, Mezzetti A, Fazia ML, Cuccurullo C, Iezzi A, Ucchino S, Spigonardo F, Bucci M, Cuccurullo F, Prescott SM, et al: Association between 5-lipoxygenase expression and plaque instability in humans. Arterioscl Throm Vas. 2005, 25 (8): 1665-1670.