Journal
CIRCULATION RESEARCH
Volume 102, Issue 8, Pages 923-932Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.169573
Keywords
vascular stiffness; eNOS uncoupling; pulse wave velocity; nitric oxide; L-arginine
Funding
- NCI NIH HHS [CA00405] Funding Source: Medline
- NIA NIH HHS [R01 AG021523] Funding Source: Medline
- NIGMS NIH HHS [R01 GM49758] Funding Source: Medline
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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.
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