title: Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice.
abstract: Peroxynitrite is an endothelium-independent vasodilator that induces relaxation via membrane hyperpolarization. The activation of IP3 receptors triggers the opening of potassium channels and hyperpolarization. Previously we found that relaxation to peroxynitrite was maintained during the development of atherosclerosis due to changes in the expression of calcium-regulatory proteins. In this study we investigated: (1) the mechanism of peroxynitrite-induced relaxation in the mouse aorta, (2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators, and (3) the effect of atherosclerosis on the expression and function of the IP3 receptor. Aortic function was studied using wire myography, and atherosclerosis was induced by fat-feeding ApoE-/- mice. The expression of IP3 receptors was studied using Western blotting and immunohistochemistry. Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2-APB and xestospongin C and also the Kv channel blocker 4-aminopyridine (4-AP). Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2-APB in atherosclerotic aortae despite the reduced expression of IP3 receptors. 4-AP was less effective in ApoE-/- mice fat-fed for 4 months. Peroxynitrite relaxation involves an IP3-induced calcium release and KV channel activation. This mechanism becomes less important as atherosclerosis develops, and relaxation to peroxynitrite may be maintained by increased calcium extrusion.
authors.forename: Marie-Ann
authors.initials: MA
authors.lastname: Ewart
authors.forename: Azizah
authors.initials: A
authors.lastname: Ugusman
authors.forename: Anisha
authors.initials: A
authors.lastname: Vishwanath
authors.forename: Tarek A M
authors.initials: TAM
authors.lastname: Almabrouk
authors.forename: Husam
authors.initials: H
authors.lastname: Alganga
authors.forename: Omar J
authors.initials: OJ
authors.lastname: Katwan
authors.forename: Pavlina
authors.initials: P
authors.lastname: Hubanova
authors.forename: Susan
authors.initials: S
authors.lastname: Currie
authors.forename: Simon
authors.initials: S
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020013:Calcium Signaling; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D030421:Peroxynitrous Acid / Q000494:pharmacology; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D053496:Inositol 1,4,5-Trisphosphate Receptors; D024642:Potassium Channels, Voltage-Gated; D014665:Vasodilator Agents; D030421:Peroxynitrous Acid
keywords: Aorta; Atherosclerosis; IP3 receptor; Peroxynitrite; Potassium channel