PMID- 25552596 OWN - NLM STAT- MEDLINE DCOM- 20150819 LR - 20220408 IS - 1939-327X (Electronic) IS - 0012-1797 (Linking) VI - 64 IP - 6 DP - 2015 Jun TI - 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. PG - 2207-19 LID - 10.2337/db14-1011 [doi] AB - 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-gamma-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. CI - (c) 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. FAU - Antonopoulos, Alexios S AU - Antonopoulos AS AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Margaritis, Marios AU - Margaritis M AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Coutinho, Patricia AU - Coutinho P AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Shirodaria, Cheerag AU - Shirodaria C AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Psarros, Costas AU - Psarros C AD - 1st Department of Cardiology, Athens University Medical School, Athens, Greece. FAU - Herdman, Laura AU - Herdman L AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Sanna, Fabio AU - Sanna F AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - De Silva, Ravi AU - De Silva R AD - Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K. FAU - Petrou, Mario AU - Petrou M AD - Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K. FAU - Sayeed, Rana AU - Sayeed R AD - Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K. FAU - Krasopoulos, George AU - Krasopoulos G AD - Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, U.K. FAU - Lee, Regent AU - Lee R AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Digby, Janet AU - Digby J AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Reilly, Svetlana AU - Reilly S AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Bakogiannis, Constantinos AU - Bakogiannis C AD - 1st Department of Cardiology, Athens University Medical School, Athens, Greece. FAU - Tousoulis, Dimitris AU - Tousoulis D AD - 1st Department of Cardiology, Athens University Medical School, Athens, Greece. FAU - Kessler, Benedikt AU - Kessler B AD - Nuffield Department of Medicine, University of Oxford, Oxford, U.K. FAU - Casadei, Barbara AU - Casadei B AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Channon, Keith M AU - Channon KM AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. FAU - Antoniades, Charalambos AU - Antoniades C AD - Cardiovascular Medicine Division, University of Oxford, Oxford, U.K. antoniad@well.ox.ac.uk. LA - eng GR - PG/13/56/30383/BHF_/British Heart Foundation/United Kingdom GR - RE/08/004/BHF_/British Heart Foundation/United Kingdom GR - FS/11/66/28855/BHF_/British Heart Foundation/United Kingdom GR - RG/12/5/29576/BHF_/British Heart Foundation/United Kingdom GR - RG/11/15/29375/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141231 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (Adiponectin) RN - EC 1.6.3.- (NADPH Oxidases) SB - IM CIN - Diabetes. 2015 Jun;64(6):1904-6. PMID: 25999534 MH - Adiponectin/*metabolism MH - Adipose Tissue/*metabolism MH - Aged MH - Arteries/*metabolism MH - Diabetes Mellitus, Type 2/*metabolism MH - Female MH - Genotype MH - Humans MH - Male MH - Middle Aged MH - NADPH Oxidases/*metabolism MH - Real-Time Polymerase Chain Reaction EDAT- 2015/01/02 06:00 MHDA- 2015/08/20 06:00 CRDT- 2015/01/02 06:00 PHST- 2014/07/03 00:00 [received] PHST- 2014/12/20 00:00 [accepted] PHST- 2015/01/02 06:00 [entrez] PHST- 2015/01/02 06:00 [pubmed] PHST- 2015/08/20 06:00 [medline] AID - db14-1011 [pii] AID - 10.2337/db14-1011 [doi] PST - ppublish SO - Diabetes. 2015 Jun;64(6):2207-19. doi: 10.2337/db14-1011. Epub 2014 Dec 31.