Statins reduce endothelial cell apoptosis via inhibition of TRAIL expression on activated CD4 T cells in acute coronary syndrome.
OBJECTIVE
Statins reduce cardiovascular-related morbidity and mortality, but their effects on inflammation in atherosclerosis are not fully understood. We investigated whether statins can modulate cytotoxic functions of CD4 T cells in acute coronary syndrome (ACS).


RESULTS
Fresh CD4 T cells were isolated from 55 patients with ACS without statin treatment on admission and from 34 age-matched controls. CD4 T cells collected from ACS patients induced endothelial cell apoptosis significantly more than control T cells. The TNF-related apoptosis-inducing ligand (TRAIL) receptor DR5 was strongly upregulated on endothelial cells, and TRAIL-specific antibodies effectively blocked CD4 T cell-mediated apoptosis, indicating that T cell-mediated endothelial death was dependent on the TRAIL pathway. Expression of both the activating antigen CD69 and TRAIL was enhanced on ACS T cells. In in-vitro assays rosuvastatin, fluvastatin, and pitavastatin directly blocked CD4 T cell-mediated endothelial cell apoptosis and reduced T cell-expression of CD69 and TRAIL through TCR-induced Extracellar signal-Regulated Kinases (ERK) activation.


CONCLUSIONS
Activated CD4 T cells expressing TRAIL are enriched in the blood of ACS patients and induce endothelial injury, which may contribute to the destabilization of the plaque. Early statin therapy may suppress T cell-mediated endothelial cell damage in atherosclerotic plaques and thus prevent cardiovascular events.
Sato
Kayoko
K
Department of Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo 162-8666, Japan. msatok@hij.twmu.ac.jp
Nuki
Toshiyuki
T
Gomita
Keiko
K
Weyand
Cornelia M
CM
Hagiwara
Nobuhisa
N
D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000378:metabolism*; D000368:Aged; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D042783:Endothelial Cells / Q000166:cytology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human