Human cytomegalovirus infection and atherothrombosis |
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Authors: | Milan Popovi? Katarina Smiljani? Branislava Dobutovi? Tatiana Syrovets Thomas Simmet Esma R Isenovi? |
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Institution: | (1) Department for Radiobiology and Molecular Genetics, Vinča Institute, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia;(2) Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, 89081 Ulm, Germany |
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Abstract: | Vascular endothelium, as a key regulator of hemostasis, mediates vascular dilatation, prevents platelet adhesion, and inhibits
thrombin generation. Endothelial dysfunction caused by acute or chronic inflammation, such as in atherosclerosis, creates
a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites, and at the same time promotes
coagulation, thrombin generation, and fibrin deposition in an attempt to close the wound. Life-long persistent infection with
human cytomegalovirus (HCMV) has been associated with atherosclerosis. In vivo studies have revealed that HCMV infection of
the vessel wall affects various cells including monocytes/macrophages, smooth muscle cells (SMCs) and endothelial cells (ECs).
HCMV-infected SMCs within vascular lesions display enhanced proliferation and impaired apoptosis, which contribute to intima-media thickening, plaque formation and restenosis. Monocytes play a central role in the process of viral dissemination, whereas
ECs may represent a viral reservoir, maintaining persistent infection in HCMV-infected atherosclerotic patients following
the primary infection. Persistent infection leads to dysfunction of ECs and activates proinflammatory signaling involving
nuclear factor κB, specificity protein 1, and phosphatidylinositol 3-kinase, as well as expression of platelet-derived growth
factor receptor. Activation of these pathways promotes enhanced proliferation and migration of monocytes and SMCs into the
intima of the vascular wall as well as lipid accumulation and expansion of the atherosclerotic lesion. Moreover, HCMV infection
induces enhanced expression of endothelial adhesion molecules and modifies the proteolytic balance in monocytes and macrophages.
As a consequence, infected endothelium recruits naive monocytes from the blood stream, and the concomitant interaction between
infected ECs and monocytes enables virus transfer to migrating monocytes. Endothelial damage promotes thrombin generation
linking inflammation and coagulation. HCMV, in turn, enhances the thrombin generation. The virus carries on its surface the
molecular machinery necessary to initiate thrombin generation, and in addition, may interact with the prothrombinase protein
complex thereby facilitating thrombin generation. Thus, infection of endothelium may significantly increase the production
of thrombin. This might not only contribute to thrombosis in patients with atherosclerosis, but might also induce thrombin-dependent
proinflammatory cell activation. This review summarizes the existing evidence on the role of HCMV in vascular inflammation. |
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