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(Circulation Research. 2009;104:1333.)
© 2009 American Heart Association, Inc.

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Angiopoietin-2 Confers Atheroprotection in apoE^–/– Mice by Inhibiting LDL Oxidation via Nitric Oxide

Asif Ahmed, Takeshi Fujisawa^*, Xi-Lin Niu^*, Shakil Ahmad^*, Bahjat Al-Ani, Kunal Chudasama, Allyah Abbas, Rahul Potluri, Vineet Bhandari, Clarence M. Findley, Gregory K.W. Lam, Jianhua Huang, Peter W. Hewett, Melissa Cudmore, Christopher D. Kontos

From the Reproductive and Vascular Biology (A. Ahmed, T.F., S.A., B.A.-A., K.C., A. Abbas, R.P., P.H., M.C.), Institute for Biomedical Research, University of Birmingham, United Kingdom; Division of Cardiology (X.-L.N., C.M.F., G.K.W.L., J.H., C.D.K.), Duke University Medical Center, Durham, NC; and Department of Pediatrics (V.B.), Yale University, New Haven, Conn.

Correspondence to Professor Asif Ahmed, Institute for Biomedical Research, University of Birmingham, Birmingham, B15 2TT, United Kingdom. E-mail a.s.ahmed{at}bham.ac.uk

Atherosclerosis is promoted by a combination of hypercholesterolemia and vascular inflammation. The function of Angiopoietin (Ang)-2, a key regulator of angiogenesis, in the maintenance of large vessels is unknown. A single systemic administration of Ang-2 adenovirus (AdAng-2) to apoE^–/– mice fed a Western diet significantly reduced atherosclerotic lesion size (40%) and oxidized LDL and macrophage content of the plaques. These beneficial effects were abolished by the inhibition of nitric oxide synthase (NOS). In endothelial cells, endothelial NOS activation per se inhibited LDL oxidation and Ang-2 stimulated NO release in a Tie2-dependent manner to decrease LDL oxidation. These findings demonstrate a novel atheroprotective role for Ang-2 when endothelial cell function is compromised and suggest that growth factors, which stimulate NO release without inducing inflammation, could offer atheroprotection.

Key Words: angiopoietin-2 • atherosclerosis • endothelial cells • LDL cholesterol • nitric oxide • nitric oxide synthases