Abstract 10940: Leptin Treatment Protects the Endothelium from Inflammation, Increased Permeability and Endothelial-to-Mesenchymal Transition

Abstract

Introduction: Patients with lipodystrophy (LD) are characterized by a loss of adipose tissue and are associated with a higher risk for cardiovascular diseases (CVD). As a consequence of adipose tissue reduction in LD patients, the systemic concentration of the adipokine leptin decreases, representing the pathological cause of this disease. Hypothesis: We hypothesized that the reduction of leptin may impair endothelial cells, leading to the development of CVD. Therefore, we analyzed the effects of leptin treatment on vascular inflammation, endothelial-to-mesenchymal transition (EndMT), endothelial permeability and atherosclerotic plaque characteristics. Methods & Results: Treatment of endothelial cells with leptin (200 ng/ml, 6 h) potently reduced IL1β-induced inflammation, as measured by expression of ICAM1 (-25.1%) and E-Selectin (-22.7%), (both p<0.05). Leptin further reduced the induction of EndMT, as determined by expression of calponin (-41.3%) and SM22 (-23.8%), (both p<0.05), as well as the EndMT-induced endothelial permeability (-20.7%, p<0.05). These data were confirmed in a combined lipodystrophic and atherosclerosis prone mouse model (LDLR -/- ;aP2-nSREBP). Treatment with leptin (3.0 mg/kg) for 8 w reduced the number of EndMT-positive endothelial cells (-69%, p<0.05) as well as the total number of mesenchymal cells in the atherosclerotic lesions (-34.8%), (both p<0.05). Further analysis of the atherosclerotic lesions revealed a reduction of atherosclerotic plaque protrusion into the vessel lumen (-31%) and reduced macrophage infiltration (-21.9%) (p<0.05), which is a hallmark of instable atherosclerotic plaques that are prone to rupture, whereas the total plaque area was not affected. The expression of the leptin receptor (LepR) was reduced in endothelial cell inflammation, EndMT (-69%, p<0.05) and in atherosclerotic lesions, suggesting reduced leptin effects under these conditions. Conclusions: Leptin treatment exerts beneficial effects protecting endothelial function and identity in lipodystrophy. Downregulation of the leptin receptor in diseased endothelial cells is likely to reduce the identified positive vascular effects of leptin signaling in lipodystrophy.