A subset of patients who have undergone coronary angioplasty develop restenosis, a vessel renarrowing characterized by excessive proliferation of smooth muscle cells (SMCs). Of 60 human restenosis lesions examined, 23 (38 percent) were found to have accumulated high amounts of the tumor suppressor protein p53, and this correlated with the presence of human cytomegalovirus (HCMV) in the lesions. SMCs grown from the lesions expressed HCMV protein IE84 and high amounts of p53. HCMV infection of cultured SMCs enhanced p53 accumulation, which correlated temporally with IE84 expression. IE84 also bound to p53 and abolished its ability to transcriptionally activate a reporter gene. Thus, HCMV, and IE84-mediated inhibition of p53 function, may contribute to the development of restenosis.

Abstract-Human cytomegalovirus (CMV) infection of smooth muscle cells generates reactive oxygen species (ROS) and thereby activates nuclear factor B (NFB), which causes expression of viral and cellular genes involved in immune and inflammatory responses. These changes could account for the mounting evidence suggesting that CMV may contribute causally to restenosis and atherosclerosis. We found that CMV induces ROS, at least partly, through a cyclooxygenase-2 (COX-2)-dependent pathway. Moreover, the viral immediate-early (IE) gene products, IE72 and IE84, have the capacity to transactivate the COX-2 promoter. Aspirin and indomethacin, both cyclooxygenase inhibitors as well as direct ROS scavengers, reduce CMV-induced ROS, probably through both of these activities. Sodium salicylate also has antiviral effects as the result of its potent antioxidant properties. Furthermore, by reducing ROS, aspirin and sodium salicylate inhibit CMV-induced NFB activation, the ability of IE72 to transactivate its promoter, CMV IE gene expression after infection of SMCs, and CMV replication in SMCs. This is the first time aspirin has been shown to have antiviral effects. Thus, it is possible that aspirin has previously unrecognized therapeutic effects in various clinical situations, such as in viral infections (when used as an antipyretic agent) and in atherosclerosis (when used as an antiplatelet agent We recently demonstrated that CMV infection of smooth muscle cells (SMCs) generates intracellular reactive oxygen species (ROS) within minutes of infection and that the resulting ROS contribute to nuclear factor B (NFB) activation.5 NFB stimulates the expression of many cellular genes and their products, including cytokines and adhesion molecules, which are involved in immune and inflammatory responses. 6 Because the CMV major immediate-early promoter (MIEP) has 4 NFB-binding sites, activation of NFB is also critical for MIEP activation and eventual expression of all viral gene products, including the immediate-early (IE) major gene product IE72. In turn, IE72 transactivates its own promoter through the multiple NFB sites. 7 Furthermore, angioplasty-induced injury to the vessel wall and reperfusion after balloon angioplasty produce ROS 8 and cytokines. The resulting activation of NFB can in turn stimulate the MIEP present in latently infected cells and thereby contribute to reactivation of latent CMV.Because of the critical role in both viral and cellular gene expression, CMV-induced ROS generation might constitute an excellent target for any therapeutic attempt to inhibit those cellular changes that are mediated by CMV infection and that might contribute to either restenosis or atherosclerosis. Indeed, we previously demonstrated that after CMV infection of SMCs, antioxidants inhibit CMV IE gene expression and viral replication.5 Further insights to refine such a strategy require identification of the cellular pathways responsible for generating ROS after CMV infection.Recent studies have shown that CMV infection of human cells 9 -11 ...

TGF-beta 1 has been examined in the heart during myocardial infarction caused by ligation of the left coronary artery. Infarcted and uninfarcted myocardium have been compared by immunohistochemical staining of TGF-beta 1 and by Northern blot analysis of mRNA. Normal ventricular myocytes are strongly stained by an antibody to TGF-beta 1. Progressive loss of staining of these myocytes begins within 1 hr after coronary ligation. However, by 24-48 hr after ligation, intense staining of myocytes at the margin of infarcted areas is seen. Northern blots of infarcted myocardium 48 hr after ligation show a 3- to 4-fold increase in the principal 2.4 kb TGF-beta 1 mRNA; there is also a marked increase in a minor 1.9 kb transcript. In the same tissue samples, there is a 2-fold decrease in the mRNA for the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase. The results indicate a significant role for TGF-beta in the response of the heart to injury.