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(Circulation Research. 2008;102:923.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Endothelial Arginase II

A Novel Target for the Treatment of Atherosclerosis

Sungwoo Ryoo^*, Gaurav Gupta^*, Alexandre Benjo, Hyun Kyo Lim, Andre Camara, Gautam Sikka, Hyun Kyung Lim, Jayson Sohi, Lakshmi Santhanam, Kevin Soucy, Eric Tuday, Ezra Baraban, Monica Ilies, Gary Gerstenblith, Daniel Nyhan, Artin Shoukas, David W. Christianson, Nicholas J. Alp, Hunter C. Champion, David Huso, Dan E. Berkowitz

From the Departments of Anesthesiology/Critical Care Medicine (S.R., A.B., H. Kyo Lim, A.C., G.S., H. Kyung Lim, E.B., D.N., D.E.B.), Biomedical Engineering (G. Gupta, J.S., L.S., K.S., E.T., A.S., D.E.B.), Medicine (G. Gerstenblith, H.C.C.), Division of Cardiology, Molecular and Comparative Pathobiology (D.H.), the Johns Hopkins Medical Institutions, Baltimore, Md; Department of Chemistry (M.I., D.W.C.), University of Pennsylvania, Philadelphia; Department of Cardiovascular Medicine (N.J.A.), John Radcliffe Hospital, University of Oxford, UK; and Institute of Long Life, Department of Anesthesiology and Pain Medicine (H. Kyung Lim), Yonsei University Wonju College of Medicine, Wonju, Korea.

Correspondence to Dan Berkowitz, MD, Associate Professor, Anesthesiology/CCM, Tower 711, The Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail dberkowi{at}bme.jhu.edu

Oxidized low-density lipoproteins increase arginase activity and reciprocally decrease endothelial NO in human aortic endothelial cells. Here, we demonstrate that vascular endothelial arginase activity is increased in atherogenic-prone apolipoprotein E–null (ApoE^–/–) and wild-type mice fed a high cholesterol diet. In ApoE^–/– mice, selective arginase II inhibition or deletion of the arginase II gene (Arg II^–/– mice) prevents high-cholesterol diet–dependent decreases in vascular NO production, decreases endothelial reactive oxygen species production, restores endothelial function, and prevents oxidized low-density lipoprotein–dependent increases in vascular stiffness. Furthermore, arginase inhibition significantly decreases plaque burden. These data indicate that arginase II plays a critical role in the pathophysiology of cholesterol-mediated endothelial dysfunction and represents a novel target for therapy in atherosclerosis.

Key Words: vascular stiffness • eNOS uncoupling • pulse wave velocity • nitric oxide • L-arginine

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