Perivascular adipose tissue supresses superoxide production in internal mammary artery grafts by regulating Rac1-mediated activation of vascular NADPH-oxidase

Abstract

Background: Internal mammary artery (IMA) is used as a graft in bypass surgery (CABG), but it is unclear whether it should be harvested with or without its perivascular adipose tissue (PVAT). Given that PVAT produces the antiatherogenic adipokine adiponectin (AdN), we examined the role of AdN as a signalling molecule between PVAT and IMA grafts. Methods: In Study 1, IMA segments were obtained from 364 patients undergoing CABG and used to determine NADPH-oxidase activity by lucigenin chemiluminescence (+/-NADPH 100μM). Mesothoracic (Mt-AT), subcutaneous (Sc-AT) and PVAT were obtained for gene expression studies. In Study 2, IMA segments from 17 patients were exposed ex vivo to AdN (10 μg/ml) for 6 hours ± wortmannin (a PI3K/Akt inhibitor); changes to NADPH-stimulated and Vas2870 (specific NADPH-oxidase inhibitor)-inhibitable O2- as well as the activation and membrane translocation of Rac1 (NADPH-oxidase subunit responsible for its activation) were determined. Results: Elevated circulating AdN was related with reduced NADPH-stimulated O2- (A). Increased expression of ADIPOQ in Mt- and Sc-AT was related with reduced NADPH-oxidase activity, however in PVAT it was associated with increased NADPH-stimulated O2-(B). AdN directly suppressed NADPH-stimulated (C) and Vas2870-inihibitable (D) O2- in the IMA. This was due to reduced activation (E)/membrane translocation (F) of Rac1, which was reversed by wortmannin. ![Figure][1] Conclusions: We demonstrate for the first time in humans, that AdN directly suppresses NADPH-oxidase through an Akt-mediated reduction of Rac1 activation and translocation to the membrane. The observed increase of AdN expression in PVAT in the presence of high oxidative stress may represent a novel, local defence mechanism of IMA against oxidative stress, that warrants further investigation. [1]: pending:yes