417회 Endothelial Arginase II; A novel Target for the Treatment of Athe…

417회 (2008. 9. 11.)

연사: 류 승 우, 강원대학교 생물학과

제목: Endothelial Arginase II; A Novel Target for the Treatment of Atherosclerosis  

Abstract 

Oxidized low-density lipoprotein (Ox-LDL) is important in the pathogenesis of atherosclerosis through mechanisms that impair NO signaling with resultant endothelial dysfunction.  Arginase (Arg), an enzyme that shares L-arginine as a substrate with NOS, reciprocally regulates NOS activity and NO production in endothelial cells. Ox-LDLs increase Arg activity by a sequence of regulatory events that involve early activation through decreased association with microtubules, and a later increase in transcription. OxLDL increase Arg activity and reciprocally decrease endothelial nitric oxide (NO) in human aortic endothelial cells. Vascular endothelial Arg activity is increased in atherogenic prone ApoE-/-and WT mice fed a high cholesterol (HC) diet. In ApoE-/- mice, arginase II inhibition with the selective  inhibitor S-(2-boronethyl)-L- cysteine (BEC) or deletion of the arginase II gene (Arg II-/- mice), prevents HC diet- dependent decreases in vascular NO production, decreases endothelial reactive oxygen species production, restores endothelial function, and prevents OxLDL-dependent increases in vascular stiffness. Furthermore, arginase inhibition in ApoE-/- mice significantly decreases plaque burden.  This data indicates that arginase II plays a critical role in the pathophysiology of cholesterol-mediated endothelial dysfunction, and represents a novel target for therapy in atherosclerosis.