Abstract 1524: HMG-CoA Reductase Inhibitors reduce Apoptosis of Endothelial Cells induced by TRAIL-expressing CD4 T cell in Acute Coronary Syndromes
Background: HMG-CoA reductase inhibitors improve atherosclerotic inflammation. However, the effects of HMG-CoA reductase on inflammation in atherosclerotic plaque are not known. In this study, we postulated that HMG-CoA reductase inhibitors might improve TRAIL-expressing CD4 T cells from acute coronary syndromes (ACS) that induce apoptosis of vascular endothelial cells.
Methods and Results: Fresh CD4 T cells were isolated from the blood obtained from patients with ACS (n=77) and from age-matched controls (n=45). T cells were co-cultured with human umbilical vein endothelial cells (HUVEC), and apoptosis was quantified by measuring fragmentation of DAPI-binding nuclear proteins. ACS-derived CD4 T cells in the acute phase effectively induced apoptosis more than 45% of HUVEC at an effector:target ratio of 10:1 compared to controls (P < 0.0001). CD4 T cells capable of inducing HUVEC apoptosis expressed high levels of CD69 and TRAIL in ACS patients with high hsCRP (P < 0.001) by FACS. TRAIL receptor DR5 was strongly detected in HUVEC susceptible to CD4 T cell-mediated apoptosis by real time PCR. Antibodies specific for TRAIL effectively blocked CD4 T cell-mediated apoptosis (P < 0.001). To examine whether HMG-CoA reductase inhibitors improve CD4 T cell-induced apoptosis of HUVEC, we treated CD4 T cells with various statins (fluvastatin, pitavastatin, atorvastatin and simvastatin). Fluvastatin and pitavastatin inhibited expression of CD69 (P < 0.0001) and TRAIL (P < 0.03) on CD4 T cells from ACS. CD4 T cell-mediated HUVEC apoptosis in ACS was blocked by fluvastatin (P < 0.002) and pitavastatin (P < 0.005) despite the prior statin treatment.
Conclusions: Vascular endothelial cells are sensitive to TRAIL-induced apoptosis. Activated CD4 T cells expressing TRAIL are enriched in the blood of ACS patients. TRAIL expressing CD4 T cells-induced vascular endothelial cell apoptosis, and HMG-CoA reductase inhibitors are highly effective in preventing T cell-mediated tissue damage in atherosclerotic plaques and cardiovascular events.