title: Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels.
abstract: BACKGROUND
  Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis.
  
  
  RESULTS
  The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2(-)) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2(-) production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2(-) and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism.
  
  
  CONCLUSIONS
  We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Marios
authors.initials: M
authors.lastname: Margaritis
authors.forename: Alexios S
authors.initials: AS
authors.lastname: Antonopoulos
authors.forename: Janet
authors.initials: J
authors.lastname: Digby
authors.forename: Regent
authors.initials: R
authors.lastname: Lee
authors.forename: Svetlana
authors.initials: S
authors.lastname: Reilly
authors.forename: Patricia
authors.initials: P
authors.lastname: Coutinho
authors.forename: Cheerag
authors.initials: C
authors.lastname: Shirodaria
authors.forename: Rana
authors.initials: R
authors.lastname: Sayeed
authors.forename: Mario
authors.initials: M
authors.lastname: Petrou
authors.forename: Ravi
authors.initials: R
authors.lastname: De Silva
authors.forename: Shapour
authors.initials: S
authors.lastname: Jalilzadeh
authors.forename: Michael
authors.initials: M
authors.lastname: Demosthenous
authors.forename: Constantinos
authors.initials: C
authors.lastname: Bakogiannis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Stefanadis
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000368:Aged; D000447:Aldehydes / Q000378:metabolism; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000601:surgery; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000378:metabolism / Q000637:transplantation; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism; D012501:Saphenous Vein / Q000378:metabolism / Q000637:transplantation; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D000447:Aldehydes; D047495:PPAR gamma; D013481:Superoxides; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C027576:4-hydroxy-2-nonenal
keywords: 5,6,7,8-tetrahydrobiopterin; adiponectin; atherosclerosis; endothelium; nitric oxide synthase type III; superoxides