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Endothelial nitric oxide synthase activation through obacunone-dependent arginase inhibition restored impaired endothelial function in ApoE-null mice.
- Source :
-
Vascular pharmacology [Vascul Pharmacol] 2014 Mar; Vol. 60 (3), pp. 102-9. Date of Electronic Publication: 2014 Feb 06. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Aorta, Thoracic drug effects
Aorta, Thoracic metabolism
Dose-Response Relationship, Drug
Endothelium, Vascular drug effects
Enzyme Activation drug effects
Enzyme Activation physiology
Enzyme Inhibitors pharmacology
Human Umbilical Vein Endothelial Cells
Humans
Male
Mice
Mice, Knockout
Organ Culture Techniques
Apolipoproteins E deficiency
Arginase antagonists & inhibitors
Arginase metabolism
Benzoxepins pharmacology
Endothelium, Vascular metabolism
Limonins pharmacology
Nitric Oxide Synthase Type III metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-3649
- Volume :
- 60
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Vascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24509132
- Full Text :
- https://doi.org/10.1016/j.vph.2014.01.006