Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

The impact of myeloperoxidase on vascular function and perivascular adipose tissue phenotype in a murine dietary obesity model
A. Hof1, M. Landerer2, J. Schäkel2, S. Geißen2, F. Nettersheim3, D. Mehrkens3, S. Baldus4, M. Adam3, M. Mollenhauer3
1Herzzentrum - Kardiologie, Universitätsklinikum Köln, Köln; 2Klinik III für Innere Medizin - Experimentelle Kardiologie, Universitätsklinikum Köln, Köln; 3Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Köln; 4Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin, Herzzentrum der Universität zu Köln, Köln;

Aim: Obesity is a main driver of cardiovascular disease in the western world and contributes substantially to cardiovascular mortality. Perivascular adipose tissue (PVAT), as an active paracrine organ, influences vascular function by secretion of vasoactive mediators. Under obese conditions, adipose tissues become inflammed and susceptible to leucocyte infiltration. Upon activation, polymorphonuclear leucocytes (PMN) release myeloperoxidase (MPO), a bactericidal heme protein involved in a variety of pathological processes within the cardiovascular system. Here, we aim to analyse the effects of MPO on phenotypical and paracrine changes of the PVAT in a murine dietary obesity model, and how these changes impact on endothelial function.


Methods:
 Male adult C57BL/6 wildtype (WT) and Mpo-/- mice were fed a 60% high fat diet (HFD) for 12 weeks, controls were fed a standard chow diet. Ultrasound examination of carotid arteries was performed and vascular strain, distensibility and pulse propagation velocity (PPV) was analyzed by VevoVasc software. PVAT, blood and aorta were harvested and vascular function was assessed in organ bath experiments by stimulating aortic rings with acetylcholine (ACh) or nitroglycerin. Blood count was performed using the Hemavet 950 system. Lipid vacuole size was measured in hematoxylin eosin stained cryosections. mRNA-expression of proinflammatory cytokines (Il-1β, MCP-1, TGFβ), adipokines (adiponectin, leptin) and adipose tissue differentiation markers were assessed by quantitative RT-PCR. 


Results:
 Weight gain of Mpo-/- mice fed a 60% HFD was significantly attenuated compared to obese WT mice. The ultrasound analysis revealed a heightened PPV as a measure of arterial stiffness and an increase in global radial strain of the carotid artery in HFD fed WT mice, but not in Mpo-/- animals. Endothelial function as measured in organ bath experiments after ACh-stimulation of aortic rings was reduced in the HFD fed WT group but normalized in HFD fed Mpo-/- mice. White blood cell count, peripheral monocytes and neutrophil count were elevated in animals fed a HFD. Lipid vacuole size within the PVAT was significantly larger in HFD fed WT mice, whereas HFD fed Mpo-/-displayed lipid vacuole sizes similar to the control cohort. In addition, mRNA-expression of the brown adipose tissue marker uncoupling protein 1 (UCP-1) was elevated in PVAT of Mpo-/- mice compared to WT mice, underlining the influence of MPO in PVAT differentiation. Furthermore, PCR results showed markedly elevated expression of proinflammatory Il-1β and TGFβ in HFD fed WT mice, but not in Mpo-/- mice. Furthermore, HFD fed Mpo-/- animals showed an increase of vasoprotective adiponectin and leptin mRNA-expression, whereas resistin mRNA-expression levels were decreased. 


Conclusion:
 In summary, loss of MPO impacts on the PVAT phenotype in a HFD-induced obesity model, fostering a brown-like adipocyte phenotype with lower expression of proinflammatory cytokines. Furthermore, the release of vasoprotective adipokines in the PVAT of Mpo-/- mice is enhanced, leading to an improved endothelial function.


https://dgk.org/kongress_programme/jt2022/aP459.html