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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1466.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Endothelial Overexpression of Fas Ligand Decreases Atherosclerosis in Apolipoprotein E–Deficient Mice

Jiang Yang; Kaori Sato; Tamar Aprahamian; Nathaniel J. Brown; Jack Hutcheson; Ann Bialik; Harris Perlman; Kenneth Walsh

From the Department of Molecular Cardiology (J.Y., K.S., T.A., A.B., K.W.), Whitaker Cardiovascular Institute, Boston University School of Medicine, and the Program in Cellular, Molecular, and Developmental Biology (J.Y., T.A., K.W.), Tufts University, Sackler School of Graduate Biomedical Sciences, Boston, Mass; and the Department of Molecular Microbiology and Immunology (N.J.B., J.H., H.P.), St. Louis University, St. Louis, Mo.

Correspondence to Kenneth Walsh, PhD, Molecular Cardiology/CVI, Boston University School of Medicine, 715 Albany St, W611, Boston, MA 02118-2526. E-mail kxwalsh{at}bu.edu

Objective— Fas ligand (FasL) can induce apoptosis in cells bearing the Fas receptor. The role of FasL in the vasculature with regard to atherosclerosis is controversial. This study examined the function of endothelial FasL during atherosclerosis.

Methods and Results— Transgenic (Tg) mice that specifically overexpress different levels of FasL on vascular endothelial cells were crossed into the apolipoprotein E–knockout background (ApoE-KO) to generate ApoE-KO/FasL–Tg mice. Although plasma cholesterol and triglyceride levels were not different between ApoE-KO/FasL–Tg mice and ApoE-KO mice after 12 weeks of a high-fat diet, overexpression of the FasL transgene significantly reduced atherosclerotic lesion area in aortae by 49%. The reduction of atherosclerotic lesion area was more pronounced in thoracic and abdominal aortae than in the aortic arch, and a 34% reduction in lesion area was observed in aortic root sections from the ApoE-KO/FasL–Tg group compared with the ApoE-KO group. Immunostaining revealed significant decreases in both macrophage and CD8 T-cell accumulation in lesions of ApoE-KO/FasL–Tg mice. ApoE-KO/FasL–Tg mice that express lower levels of endothelial FasL also displayed reduced lesion size, but this reduction was statistically significant at the aortic arch only.

Conclusions— Overexpression of endothelial FasL is antiinflammatory and inhibits atherosclerosis under hypercholesterolemic conditions.

Fas ligand (FasL) can induce apoptosis in cells bearing the Fas receptor. This study examined the function of endothelial FasL during atherosclerosis. Overexpression of endothelial FasL transgene significantly reduced atherosclerotic lesion areas in aortae. Overexpression of endothelial FasL is antiinflammatory and inhibits atherosclerosis under hypercholesterolemic conditions.

Key Words: atherosclerosis • inflammation • endothelium • Fas ligand • transgene

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