Leptin inhibits endothelial-to mesenchymal transition in lipodystrophic mice and in endothelial cells

Background Lipodystrophy (LD) patients are characterized by reduced leptin levels and often suffer from cardiovascular diseases (CVD). An important disease mechanism in CVD is endothelial-to-mesenchymal transition (EndMT), the transformation of an endothelial to a mesenchymal cell. EndMT is found in instable atherosclerotic plaques that are prone to rupture. The treatment of LD patients with recombinant leptin is a promising therapeutic option. Objective The aim was to evaluate for the first time whether EndMT occurs in LD using a LD mouse model (LDLR-/-;aP2-nSREBP) and whether EndMT is affected by leptin treatment. Methods and Results We found increased EndMT and protrusion of atherosclerotic plaques in LD mice. Leptin treatment (3.0 mg/kg) for 8 w reduced EndMT positive cells in plaques of the aortic root (-69%) (p<0.05). Also, leptin treatment decreased macrophage infiltration (-21.9%) and plaque protrusion into the vessel lumen (-31%) (p<0.05). These findings were confirmed in an in vitro EndMT model using primary human endothelial cells, where leptin treatment (100 ng/ml, 72 h) also led to a decrease in the EndMT markers calponin (-41.3%) and SM22 (-23.8%) (p<0.05). Finally, we validated the beneficial effects of leptin treatment using single cell sequencings of endothelial cells undergoing EndMT, where leptin treatment reduced the EndMT marker expression per cell. Conclusion We identified EndMT as a potential CVD mechanism in LD for the first time. Treatment of LD mice with leptin reduced EndMT in vivo and in vitro and positively affected parameters of atherosclerosis in vivo. Publication History Article published online: 26 May 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany