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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Latent infection of vascular cells with herpes-viruses may play a pathogenic role in the development of human atherosclerosis. In a previous study, we found that cultured human umbilical vein endothelial cells (HUVECs) infected with herpes simplex virus 1 (HSV-1) became procoagulant, exemplified both by their enhanced assembly of the prothrombinase complex and by their inability to reduce adhesion of platelets. We now report two further procoagulant consequences of endothelial HSV infection: loss of surface thrombomodulin (TM) activity and induction of synthesis of tissue factor. Within 4 hr of infection of HUVECs, TM activity measured by thrombin-dependent protein C activation declined 21 +/- 3% (P less than 0.05) and by 18 hr, 48 +/- 5% (P less than 0.001). Similar significant TM decrements accompanied infection of bovine aortic endothelial cells. Identical TM loss was induced with HSV-2 infection but not with adenovirus infection. Decreased surface expression of TM antigen (measured by the specific binding of a polyclonal antibody to bovine TM) closely paralleled the loss of TM activity. As examined by Northern blotting, these losses apparently reflected rapid onset (within 4 hr of HSV infection) loss of mRNA for TM. In contrast, HSV infection induced a viral-dose-dependent increase in synthesis of tissue factor protein, adding to the procoagulant state. The results indicate that loss of endothelial protein-synthetic capacity is not a universal effect of HSV infection. We suggest that the procoagulant state induced by reduction in TM activity and amplified tissue factor activity accompanying HSV infection of endothelium could contribute to deposition of thrombi on atherosclerotic plaques and to the "coagulant-necrosis" state that characterizes HSV-infected mucocutaneous lesions.
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PMID:Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. 216 19

Herpes simplex virus (HSV) infection may be involved in various endothelial-injury syndromes, including vasculitis and atherosclerosis. In a previous study, it was reported that HSV-infected human umbilical endothelial cells are more vulnerable to detachment mediated by granulocyte-secreted proteases. To elucidate the molecular basis of this observation, the authors examined the interaction of infected endothelial cells with the purified basement membrane proteins, fibronectin, laminin, and type IV collagen. HSV-infected endothelial cells exhibited defects in their ability to adhere, spread, and migrate on all three matrix components. This defective adhesion could be partially overcome by increasing concentrations of fibronectin; in contrast, no abrogation of deficient binding occurs with increased levels of laminin or collagen type IV. This suggests that endothelial cells may use different surface constituents for binding to the three proteins and use multiple "receptors" for adhesion to the fibronectin molecule--"receptors" that are variably affected by HSV infection. The authors investigated this supposition by assaying adhesion of normal and infected endothelial cells to two non-overlapping cell-adhesion promoting fragments of fibronectin: 1) a 75 kd motility-promoting fragment which contains the arginyl-glycyl-aspartylserine (RGDS) adhesion sequence, and 2) a 33 kd carboxyl-terminal heparin binding fragment, which promotes cell adhesion by an RGDS-independent mechanism. Normal endothelial cells adhered and spread on both purified fragments. In contrast, while infected endothelial cells could adhere, albeit rather poorly, to high coating concentrations of the 75 kd fragment, these cells did not bind to the 33 kd heparin binding fragment of fibronectin at all. These results support the concept that endothelial cells adhere to multiple domains of fibronectin, and that HSV infection preferentially abrogates binding to the heparin-binding domain, while leaving relatively intact receptors for the RGDS-containing domain. In support, soluble RGDS significantly blocked fibronectin adhesion of infected, but not control, endothelial cells. It is concluded that HSV infection inhibits the interaction of endothelial cells with basement membrane proteins and weakens their tethering to substratum. This tethering is inadequate for proper cell spreading or movement to occur and may result in both excessive endothelial lift-off and impaired vascular repair in HSV infections.
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PMID:Herpes simplex virus inhibits endothelial cell attachment and migration to extracellular matrix proteins. 253 23

Some endothelial-injury syndromes, including atherosclerosis, may involve herpes simplex virus (HSV) infection. Examining the mechanism of injury, we found adherence of unstimulated granulocytes to HSV infected endothelium to be twice that to uninfected endothelium (34.8 +/- 1.1 versus 18.8 +/- 0.5%; mean +/- SEM; p less than 0.001) which further increased in the presence of anti-HSV antibodies. Enhanced adhesion was accompanied by excessive granulocyte-mediated lysis of 51Cr-labeled, HSV-infected endothelium (16.4 +/- 0.9%, HSV-infected versus 0.9 +/- 4.5% for uninfected endothelium; p less than 0.01). HSV infection also increased granulocyte-mediated endothelial cell detachment from its substratum (14.7 +/- 1.7% versus 3.3 +/- 0.3% for uninfected endothelium; p less than 0.001), which further increased (p less than 0.01) in the presence of immune complexes (IgG-sensitized erythrocytes). This suggests that neo-Fc receptors of infected endothelium bind IgG-coated particles, which, in turn, attract and stimulate granulocytes. In support, granulocyte-mediated detachment was not enhanced by immune complexes if endothelium was infected with a mutant HSV strain (E3/3) that does not produce glycoprotein E, the viral glycoprotein having Fc-receptor activity. Exaggerated endothelial detachment correlated with poor binding of infected endothelial cells to the substratum matrix protein, fibronectin. Resuspended, virus-infected endothelial cells bound significantly less well to tissue-culture wells coated with both low (p less than 0.001) and high (p less than 0.05) concentrations of fibronectin as compared with uninfected endothelial cells, a dichotomy further worsened in the presence of granulocyte-released elastase. We conclude that HSV-infected human endothelium is vulnerable to granulocyte-mediated injury by opposing alterations in its adhesive properties: its increased binding of granulocytes and its weakened tethering to matrix fibronectin, particularly when exposed to secreted granulocyte proteases, such as elastase.
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PMID:Granulocyte-mediated injury to herpes simplex virus-infected human endothelium. 253 63

This paper presents a brief overview of our current understanding of the relationship between herpes simplex virus (HSV) and atherogenesis. In the search for a viral trigger of atherosclerosis, several investigators reported the detection of herpes simplex virus in some, but not all atherosclerotic lesions. HSV infections are very common, not only in atherosclerotic patients but also in the general population, making epidemiological studies difficult to interpret. Different mechanisms by which HSV may contribute to atherogenesis have been described. In vascular cells, HSV infection leads to lipid accumulation. HSV infection of endothelial cells attracts leukocytes with subsequent inflammatory damage; it activates procoagulant changes on endothelium with increased thrombin generation and platelet adhesion, and changes its interaction with extracellular matrix proteins. Future studies should delineate whether these mechanisms are operative in the pathogenesis of atherosclerosis.
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PMID:Herpes simplex virus and atherosclerosis. 813 86