Abstract 1209 Leptin treatment reduces EndMT and has vasculo-protective effects in lipodystrophic mice

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Leptin treatment reduces EndMT and has vasculo-protective effects in lipodystrophic mice
P. Stürzebecher¹, S. Kralisch², M. R. Schubert¹, V. Filipova¹, A. Hoffmann², M. Blüher², K. Miehle², T. Ebert², M. Fasshauer³, U. Laufs¹, A. Tönjes², J.-N. Boeckel¹
¹Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig; ²Klinik und Poliklinik für Endokrinologie, Nephrologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig; ³Institut für Ernährungswissenschaft, Justus-Liebig-Universität Giessen, Gießen;
Introduction and Hypothesis: The large amounts of adipose tissue present with obesity are associated with increased levels of the adipokine leptin but comparatively low leptin effects. In contrast, the disease group lipodystrophy syndromes (LD) is characterized by a loss of adipose tissue and an associated deficiency of leptin. Obesity as well as LD lead to the same metabolic disturbances and premature atherosclerosis. Leptin replacement therapy is a current treatment option for LD patients that reduces the risk of death. Results of studies on the effect of leptin substitution on the development and progression of atherosclerosis in LD patients are currently pending. We investigate the hypothesis that leptin limits atherosclerosis by positive effects on the vascular system using a combined lipodystrophic and atherosclerosis-prone mouse model (LDLR^-/-;aP2-nSREBP). Methods and Results: Leptin treatment reduced endothelial cell (EC) inflammation (ICAM-1, -5.2-fold control, p<0.05) as well as endothelial to mesenchymal transition (EndMT) (SM22, -2.3-fold control, p<0.05) at mRNA and protein level as determined by immunofluorescence. The positive effect of leptin on EndMT was subsequently confirmed by single cell sequencing. To investigate a possible role of leptin in the development of atherosclerosis, we used a combined lipodystrophic and atherosclerosis-prone mouse model (LDLR^-/-;aP2-nSREBP). Analysis of histological sections of the aortic roots showed a reduction in the protrusion of atherosclerotic lesions into the vessel lumen (-31%, p<0.05, n=4-6) by leptin treatment. In concordance to the in vitro results, leptin treatment reduced the number of ECs undergoing EndMT (-3.28%, p<0.05, n=4-6) in atherosclerotic lesions. Consistent with the decreased permeability of the endothelial layer in vitro (-10.8-fold, p<0.05, n=3), a reduction in macrophage infiltration (-21.9%, p<0.05, n=10-11) into the atherosclerotic lesions was observed after leptin treatment. Interestingly, the expression of the leptin receptor was reduced by EC inflammation, EndMT (-69%, p<0.05, n=3) and in atherosclerotic lesions. Conclusions: Leptin treatment reduces endothelial inflammation, permeability, and EndMT in vitro. In lipodystrophic mice, leptin treatment limits atherosclerotic processes, although the expression of the executive receptor is reduced by inflammation and EndMT. In addition to ameliorating the metabolic complications of LD, leptin treatment may be beneficial for endothelial identity and function and for the vasculature in LD but also metabolic-induced cardiovascular disease.
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