title: Oxidized low-density lipoprotein inhibits nitric oxide-mediated coronary arteriolar dilation by up-regulating endothelial arginase I.
abstract: Oxidized low-density lipoprotein (OxLDL) causes impairment of endothelium-dependent, nitric oxide (NO)-mediated vasodilation involving l-arginine deficiency. However, the underlying mechanism remains elusive. Since arginase and endothelial NO synthase (eNOS) share the substrate l-arginine, we hypothesized that OxLDL may reduce l-arginine availability to eNOS for NO production, and thus vasodilation, by up-regulating arginase. To test this hypothesis, porcine subepicardial arterioles (70-130 μm) were isolated for vasomotor study and for immunohistochemical detection of arginase and eNOS expressions. The coronary arterioles dilated dose-dependently to the endothelium-dependent NO-mediated vasodilator serotonin. This vasodilation was inhibited in the same manner by NOS inhibitor N(G)-nitro-l-arginine methyl ester and by lumenal OxLDL (0.5 mg protein/mL). The inhibitory effect of OxLDL was reversed after treating the vessels with either l-arginine (3 mM) or arginase inhibitor difluoromethylornithine (DFMO; 0.4 mM). Consistent with vasomotor alterations, OxLDL inhibited serotonin-induced NO release from coronary arterioles and this inhibition was reversed by DFMO. Vascular arginase activity was significantly elevated by OxLDL. Immunohistochemical analysis indicated that OxLDL increased arginase I expression in the vascular wall without altering eNOS expression. Taken together, these results suggest that OxLDL up-regulates arginase I, which contributes to endothelial dysfunction by reducing l-arginine availability to eNOS for NO production and thus vasodilation.
authors.affiliation: Department of Systems Biology and Translational Medicine, College of Medicine, Texas A&M Health Science Center, Temple, Texas 76504, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
authors.forename: David C
authors.initials: DC
authors.lastname: Zawieja
authors.forename: James C
authors.initials: JC
authors.lastname: Liao
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis*; D001120:Arginine / Q000378:metabolism*; D003331:Coronary Vessels / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D001119:Arginase