Abstract 492: Adipolin/C1q/Tnf-related Protein 12 reduces Neointimal Formation And Atherosclerotic Lesion Development By Modulation Of Macrophage Inflammatory Response And Endothelial Cell Function

Objectives: Obesity is causally linked to the progression of vascular disorders including atherosclerosis and post-angioplasty restenosis. Recently, we identified adipolin/C1q/Tnf-related protein 12 as an insulin sensitizing adipokine,which is downregulated in rodent models of obesity. Here, we investigated whether adipolin modulates the development of vascular diseases using loss-of-function genetic manipulations. Methods and Results: Under basal conditions, no significant differences were observed in body weight, organ weights, blood pressure and fasting plasma glucose levels between wild-type (WT) and adipolin-knockout (APL-KO) mice. APL-KO mice exhibited enhanced neointimal thickening after femoral artery injury compared with WT mice, which was accompanied by increased expression levels of pro-inflammatory mediators including tumor necrosis factor (TNF)-α and interleukin (IL)6 in injured vessels. Conversely, systemic administration of adipolin to WT mice using adenoviral vector expression systems ameliorated injury-induced neointimal thickening and inflammatory response. APL-KO mice also showed impaired re-reendothelialization after vascular injury compared with WT mice. Furthermore, adipolin deficiency increased atherosclerotic lesion area in an apolipoprotein E-knockout mouse model, which was accompanied by enhanced inflammatory response in the arterial vessel walls. Treatment of cultured macrophages with recombinant adipolin protein attenuated lipopolysaccharide-stimulated expression of inflammatory mediators, such as TNF-α and IL6. The anti-inflammatory actions of adipolin in macrophages were reversed by inhibition of transforming growth factor-β receptor II (TGF-βRII)/Smad2 signaling. In addition, treatment of human umbilical vein endothelial cells with adipolin protein promoted migratory activity and reduced serum starvation-induced apoptosis. Conclusion: These data suggest that adipolin suppresses injury-induced neointimal formation and atherosclerosis development through its abilities to modulate macrophage inflammatory responses and endothelial cell functions in vascular walls.