Published online before print May 21, 2009, doi: 10.1161/CIRCRESAHA.109.196154
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Submitted on March 6, 2009
Revised on April 27, 2009
Accepted on May 12, 2009
Angiopoietin-2 Confers Atheroprotection in ApoE-/- Mice by Inhibiting LDL Oxidation via Nitric Oxide
Asif Ahmed *;
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.
* To whom correspondence should be addressed. 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. Nitric oxide synthase (NOS) inhibitor abolished these beneficial effects of Ang-2. 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 in which 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