Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway

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Aims—Perivascular adipose tissue (PVAT) is recognized for its vaso-active effects, however it’s unclear how Metabolic Syndrome impact thoracic-aorta (t)PVAT and the subsequent effect on functional and structural aortic stiffness. Methods & Results—Thoracic aorta and tPVAT were removed from 16–17 week old lean (LZR, n=16) and obese Zucker (OZR, n=16) rats. OZR presented with aortic endothelial dysfunction, assessed by wire-myography, and increased aortic stiffness, assessed by elastic modulus. OZR-tPVAT exudate further exacerbated the endothelial dysfunction reducing nitric oxide and endothelial dependent relaxation (p <0.05). Additionally, OZR-tPVAT exudate had increased MMP9 activity (p<0.05) and further increased elastic modulus of the aorta following 72- hours of coculture (p<0.05). We found the observed aortic dysfunction caused by OZR-tPVAT was mediated through increased production and release of TNFα (p<0.01), which was dependent on tPVAT NADPH-oxidase 2 (NOX2) activity. OZR-tPVAT ROS and subsequent aortic dysfunction was inhibited by TNFα neutralization and/ or inhibition of NOX2. Additionally, we found OZRtPVAT had reduced activity of the 20S proteasome’s active sites (p<0.05) and reduced superoxide dismutase activity (p<0.01). Conclusion—Metabolic syndrome causes tPVAT dysfunction through interplay between TNFα and NOX2 leading to tPVAT mediated aortic stiffness by activation of aortic ROS and increased MMP9 activity.