title: Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue.
abstract: Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase-derived superoxide anions (O2˙(-)). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase-derived O2˙(-). However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase-derived O2˙(-). Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22(phox) through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-γ-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Alexios S
authors.initials: AS
authors.lastname: Antonopoulos
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Marios
authors.initials: M
authors.lastname: Margaritis
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Patricia
authors.initials: P
authors.lastname: Coutinho
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Cheerag
authors.initials: C
authors.lastname: Shirodaria
authors.affiliation: 1st Department of Cardiology, Athens University Medical School, Athens, Greece.
authors.forename: Costas
authors.initials: C
authors.lastname: Psarros
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Laura
authors.initials: L
authors.lastname: Herdman
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sanna
authors.affiliation: Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K.
authors.forename: Ravi
authors.initials: R
authors.lastname: De Silva
authors.affiliation: Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K.
authors.forename: Mario
authors.initials: M
authors.lastname: Petrou
authors.affiliation: Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K.
authors.forename: Rana
authors.initials: R
authors.lastname: Sayeed
authors.affiliation: Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K.
authors.forename: George
authors.initials: G
authors.lastname: Krasopoulos
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Regent
authors.initials: R
authors.lastname: Lee
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Janet
authors.initials: J
authors.lastname: Digby
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Reilly
authors.affiliation: 1st Department of Cardiology, Athens University Medical School, Athens, Greece.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Bakogiannis
authors.affiliation: 1st Department of Cardiology, Athens University Medical School, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.affiliation: Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. antoniad@well.ox.ac.uk.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000368:Aged; D001158:Arteries / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D052242:Adiponectin; D019255:NADPH Oxidases