Abstract 1371: TNFα Renders Vascular Smooth Muscle Cells in the Atherosclerotic Plaque Susceptible to Apoptosis by Inducing the Expression of Death Receptor 5
Background: Induction of apoptosis of vascular smooth muscle cells in the fibrous cap by plaque-infiltrating TRAIL-expressing CD4 T cells is an important mechanism of plaque instability. In this study, we hypothesized that TNFα enhances the expression of the TRAIL ligand DR5 on vascular smooth muscle cells in the atherosclerotic plaque and contributes to its proneness to rupture.
Methods and Results: TNFα transcripts were strongly expressed in the carotid atherosclerotic plaques (n=21) compared to control carotid arteries (n=10) as determined by real-time PCR (P < 0.003). TNFα enhanced CD4 T cell-induced apoptosis of coronary artery smooth muscle cells (CASMC) in a co-culture system. Western blot analysis showed that TNFα efficiently induced DR5 expression in CASMC. T cell numbers in the carotid artery plaque closely correlated with TNFα (R =0.550, P < 0.01) and DR5 transcripts (R =0.493, P < 0.02). Pretreatment of CD4 T cells from acute coronary syndrome patients with anti-TNFα mAb blocked apoptosis of CASMC (P < 0.005), indicating that TNFα is in part produced by tissue-infiltrating T cells. In further support of this hypothesis, CD4 T cells induced DR5 expression in CASMC in a co-culture system (P < 0.0001).
Conclusions: Our data suggest that TNFα, in part produced by T cells, induces DR5 expression on vascular smooth muscle cells, rendering them susceptible to TRAIL-mediated apoptosis. Local TNFα production in the atherosclerotic plaque may be a risk factor for plaque vulnerability by enabling the TRAIL - DR5 pathway.