Endothelial arginase II: a novel target for the treatment of atherosclerosis.
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.
Ryoo
Sungwoo
S
Department of Anesthesiology/Critical Care Medicine, the Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Gupta
Gaurav
G
Benjo
Alexandre
A
Lim
Hyun Kyo
HK
Camara
Andre
A
Sikka
Gautam
G
Lim
Hyun Kyung
HK
Sohi
Jayson
J
Santhanam
Lakshmi
L
Soucy
Kevin
K
Tuday
Eric
E
Baraban
Ezra
E
Ilies
Monica
M
Gerstenblith
Gary
G
Nyhan
Daniel
D
Shoukas
Artin
A
Christianson
David W
DW
Alp
Nicholas J
NJ
Champion
Hunter C
HC
Huso
David
D
Berkowitz
Dan E
DE
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D002784:Cholesterol / Q000008:administration & dosage; D042783:Endothelial Cells / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D015854:Up-Regulation; D014655:Vascular Resistance
D001057:Apolipoproteins E; D009569:Nitric Oxide; D002784:Cholesterol; D052250:Nitric Oxide Synthase Type III; C481673:Arg2 protein, mouse; D001119:Arginase