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Circulation Research. 2008
Published online before print February 28, 2008, doi: 10.1161/CIRCRESAHA.107.169573
A more recent version of this article appeared on April 25, 2008
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Submitted on April 28, 2007
Revised on January 31, 2008
Accepted on February 20, 2008

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 ; and 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 Department of Anesthesiology and Pain Medicine (H. Kyung Lim), Inha University College of Medicine, Incheon, Korea.

* To whom correspondence should be addressed. 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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