title: Endothelial nitric oxide synthase activation through obacunone-dependent arginase inhibition restored impaired endothelial function in ApoE-null mice.
abstract: Endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) by substrate depletion and reduces nitric oxide bioavailability. During the screening course of arginase inhibitor, we found obacunone as an arginase inhibitor. We tested the hypothesis that obacunone regulates vascular endothelial NO production. Obacunone incubation inhibited arginase I and II activities in liver and kidney lysates, respectively, in dose-dependent manner. Obacunone reciprocally increased nitrite/nitrate (NOx) production in HUVECs. In isolated aortic rings, obacunone increased intracellular l-arginine concentration and enhanced eNOS coupling, leading to increased NO and decreased superoxide production, with no changes in protein expression. Vasoconstriction response to U46619 was attenuated in obacunone-treated aortic vessels compared to that in untreated vessels. Endothelium-dependent vasorelaxant response to acetylcholine was significantly increased in obacunone-treated vessels and was modulated by the NO-dependent signaling cascade. The dose-dependent vasorelaxant response to Ach was reduced in the aortic vessels of ApoE-/- mice fed a high-cholesterol diet. Obacunone incubation increased vasorelaxation to the level of a WT mouse, although the endothelium-independent response to sodium nitroprusside was identical among the groups. Therefore, obacunone may help treat cardiovascular diseases derived from endothelial dysfunction and may be useful for designing pharmaceutical compounds.
authors: Department of Biology, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Jeongyeon
authors: J
authors: Yoon
authors: Department of Biology, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Minjin
authors: M
authors: Park
authors: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors: Jeong hyung
authors: Jh
authors: Lee
authors: College of Pharmacy, Catholic University, Daegu 712-702, Republic of Korea.
authors: Byung Sun
authors: BS
authors: Min
authors: Department of Biology, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea. Electronic address: ryoosw08@kangwon.ac.kr.
authors: Sungwoo
authors: S
authors: Ryoo
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001584:Benzoxepins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036701:Limonins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009924:Organ Culture Techniques
chemical_list: D001057:Apolipoproteins E; D001584:Benzoxepins; D004791:Enzyme Inhibitors; D036701:Limonins; C067207:obacunone; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D001119:Arginase
keywords: Arginase; Endothelial function; Endothelial nitric oxide synthase; Nitric oxide; Obacunone