Lysis of Human Arterial Smooth Muscle Cells Infected with Herpesviridae by Peripheral Blood Mononuclear Cells: Implications for Atherosclerosis

Abstract

The cytotoxicity of peripheral blood mononuclear cells (PBMC) to human arterial smooth muscle cells (SMC) infected with cytomegalovirus (CMV) or herpes simplex virus-1 (HSV) was investigated. PBMC were isolated from heparinized blood of healthy donors by Ficoll-Hypaque centrifugation and were tested for cytotoxicity against human SMC or human fibroblast-like (MRC-5) cells infected with CMV or HSV, using the chromium-51 (51Cr) release cytotoxicity assay. Both SMC and MRC-5 cells infected with either CMV (SMC-CMV), (MRC-5-CMV), or HSV (SMC-HSV), (MRC-5-HSV) were lysed by PBMC above background lysis of uninfected SMC cells. Treatment of PBMC with NK-specific monoclonal CD16 antibody and rabbit complement reduced greatly the lysis of SMC, SMC-CMV, and K562 cells, suggesting that lysis of different types of target cell by PBMC was mediated mainly by natural killer (NK) cells. The pattern of natural cytotoxicity against SMC-CMV was different from that against SMC-HSV. Maximum lysis of SMC-CMV was observed at 24 hr postinfection compared to 8 hr postinfection for SMC-HSV. NK reactivity against SMC-CMV increased from 8 to 24 hr postinfection, followed by a gradual decline at 48 and 72 hr. Supernatants generated by culturing SMC-CMV or coculturing SMC-CMV with PBMC enhanced NK cell-mediated lysis of SMC or SMC-CMV. Natural cytotoxic reactivities of PBMC against SMC-CMV or SMC-HSV may occur in vivo. Such reactions could moderate the interaction of these viruses with vascular SMC and could influence the development and/or the progression of atherosclerotic lesions.

Infections and the Cardiovascular System: New Perspectives

“…Optimal treatment of infected pacemaker and implantable defibrillator devices involves complete removal of all hardware, followed by antibiotic therapy and early reimplantation at a new site 109,[113][114][115][116] . Patients with lead infection or device associated endocarditis should receive intravenous therapy for 28 days.…”

“…It has been proposed that homocysteine-induced endothelial injury exposes the subendothelial matrix, leading to platelet activation, as homocysteine-induced atherosclerosis is characterized by substantial platelet accumulation and platelet thrombus 115,116 . In primates hyperhomocysteinemia leads to impaired vasomotor regulation and endothelial antithrombotic function 117 and similar findings are presenting in young patients with hyperhomocysteinemia and peripheral vascular disease 118 .…”

“…Furthermore, antithrombin acts as a negative acute-phase protein and its synthesis is diminished 100,113 . LPS and can interact with the endothelium to downregulate thrombomodulin 110,114 , activated neutrophils can also release elastase which can cleave thrombomodulin 115 and decreases its function by releasing reactive oxygen species, through oxidation of methionine on thrombomodulin 116 . These mechanisms lead to decreased thrombin inactivation and decreased generation of activated protein C. With complement activation and cytokine secretion, the serum level of C4bbinding increases and diminishes free protein S for supporting activated protein C 117 .…”

“…A few studies used immune complex assays 58,60,63 , or measured chlamydial-LPS antibodies (genus-specific), or chlamydial heat shock protein-60 (CHSP-60) antibodies 82,100 (see Table 5.5). Seven studies assessed the relationship between C. pneumoniae DNA in PBMC and vascular disease 50,51,52,99,103,115,117 and single studies found association with antibodies to specific C. pneumoniae antigen by immunoblotting 92 and by cell mediated immune (CMI) response 97 . Overall 38 (63.3%) of the studies using different techniques found a positive association with C. pneumoniae infection and atherosclerotic vascular disease.…”

“…Both HSV and CMV can infect vascular smooth cells 115,116 and CMV can initiate viral replication within coronary smooth-muscle cells 117 . Vascular cells generate reactive oxygen species in response to stress, and this may lead to increased transcription of atherosclerosis related cellular and viral genes and to reactivation of latent viral infection.…”