title: Periadventitial adipose tissue impairs coronary endothelial function via PKC-beta-dependent phosphorylation of nitric oxide synthase.
abstract: Endogenous periadventitial adipose-derived factors have been shown to contribute to coronary vascular regulation by impairing endothelial function through a direct inhibition of endothelial nitric oxide synthase (eNOS). However, our understanding of the underlying mechanisms remains uncertain. Accordingly, this study was designed to test the hypothesis that periadventitial adipose tissue releases agents that attenuate coronary endothelial nitric oxide production via a protein kinase C (PKC)-beta-dependent mechanism. Isometric tension studies were conducted on isolated canine circumflex coronary arteries with and without natural amounts of periadventitial adipose tissue. Adipose tissue significantly diminished coronary endothelial-dependent vasodilation and nitric oxide production in response to bradykinin and acetylcholine. The selective inhibition of endothelial PKC-beta with ruboxistaurin (1 microM) abolished the adipose-induced impairment of bradykinin-mediated coronary vasodilation and the endothelial production of nitric oxide. Western blot analysis revealed a significant increase in eNOS phosphorylation at the inhibitory residue Thr(495) in arteries exposed to periadventitial adipose tissue. This site-specific phosphorylation of eNOS was prevented by the inhibition of PKC-beta. These data demonstrate that periadventitial adipose-derived factors impair coronary endothelial nitric oxide production via a PKC-beta-dependent, site-specific phosphorylation of eNOS at Thr(495).
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Payne
authors.forename: H Glenn
authors.initials: HG
authors.lastname: Bohlen
authors.forename: U Deniz
authors.initials: UD
authors.lastname: Dincer
authors.forename: Léna
authors.initials: L
authors.lastname: Borbouse
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology; D003331:Coronary Vessels / Q000502:physiology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010496:Pericardium / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D064546:Protein Kinase C beta
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D009569:Nitric Oxide; C099154:ruboxistaurin; D052250:Nitric Oxide Synthase Type III; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D001920:Bradykinin; C064758:Ro 31-8220