1Universitätsklinikum Köln Herzzentrum - Kardiologie Köln, Deutschland; 2Universitätsklinikum Köln Klinik III für Innere Medizin - Experimentelle Kardiologie Köln, Deutschland; 3Asklepios Klinikum Harburg I. Medizinische Abteilung, Kardiologie Hamburg, Deutschland; 4Universitätsklinikum Bonn Institut für Pharmakologie und Toxikologie Bonn, Deutschland; 5Herzzentrum der Universität zu Köln Klinik III für Innere Medizin Köln, Deutschland; 6Herzzentrum der Universität zu Köln Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin Köln, Deutschland
Background: Obesity, one of the most challenging conditions in western societies, largely contributes to the development of cardiovascular disease and provokes pro-inflammatory activation of adipose tissues. Perivascular adipose tissue (PVAT) surrounds the arterial wall and directly modulates vascular function in a paracrine manner. In obesity, immune cells, including myeloperoxidase (MPO)-releasing myeloid cells, accumulate in PVAT. The impact of neutrophil-derived MPO on PVAT in obesity and subsequent effects on endothelial function are unknown.
Methods: In 46 obese patients, plasma levels of MPO, IL-6 and CRP were measured and endothelial function was assessed by flow-mediated dilation (FMD) before and three months after bariatric surgery. Inflammatory activation, adipocyte beiging and adiponectin (APN) secretion in PVAT was investigated in a genetically inherited (GIO) and a dietary induced (DIO) mouse model of obesity in MPO-deficient (Mpo-/-) mice and littermate controls. Vascular function was assessed by carotid ultrasound and organ bath experiments. In vitro, beiging of subcutaneous human white adipocytes (sHWAs) was induced by noradrenaline and cold exposure. The inflammatory activation, phenotypic changes, and vascular mediator secretion were assessed in beige sHWAs upon incubation with MPO.
Results: MPO plasma levels correlated with body weight and vascular FMD in obese patients and in plasma and PVAT of obese mice. MPO deficiency reduced immune cell infiltration and fostered beiging of PVAT via induction of soluble guanylyl cyclase β1 (sGC-β1). Nitrotyrosine formation and proinflammatory cytokine release were attenuated in obese Mpo-/- mice. APN secretion was induced in PVAT of obese Mpo-/- mice, which rescued endothelial function and reduced arterial stiffness in obesity. In vitro, MPO treated sHWAs presented less expression of APN and brown adipocyte markers but enhanced pro-inflammatory cytokine production. Our data confirm a relevance of APN for improved endothelial function in obesity-associated endothelial dysfunction. Endothelial function of APN-deficient (Adipoq-/-) aortic rings was reconstituted when incubated with supernatant from Mpo-/- derived PVAT compared to controls. In contrast, incubation of Mpo-/- aortic rings with supernatant from Adipoq-/- derived PVAT impaired endothelial function.
Conclusion: In obesity, MPO impairs vascular function via pro-inflammatory activation of PVAT, suppression of vasoprotective mediator secretion and attenuation of adipocyte beiging by inhibition of sGC- β1.