Abstract 12277: Angiopoietin-Like Protein2 (angptl2)-Induced Vascular Inflammation Causes the Progression of Endothelial Dysfunction and Atherosclerosis
Chronic vascular inflammation in coronary artery plays crucial roles in pathogenesis of coronary artery disease, however the molecular mechanisms have not been fully clarified. Recently, we reported that adipose tissue-derived Angptl2, which promotes vascular inflammation through activating the integrin α5β1/Rac1/NF-κB pathway, is a key mediator linking obesity to adipose tissue inflammation and systemic insulin resistance (Cell Metabolism 2009). Recently, we found the expression of Angptl2 in endothelial cells and macrophages in human coronary atheromatous plaque by immunohistochemical analysis. To further investigate the role of endothelial cells-derived Angptl2 in the atherosclerosis, we generated transgenic mice expressing Angptl2 driven by the endothelium-specific promoter Tie2 (Tie-2-Angptl2). Firstly, RT-PCR analysis revealed that chronic vascular inflammation exist in Tie-2-Angptl2 transgenic mice compared to wildtype mice. Acetylcholine (ACh)-induced vasorelaxation was impaired in isolated descending thoracic aortas from Tie-2-Angptl2 transgenic mice compared with wildtype mice (61.42±3.06% vs. 90.59±3.10% relaxation at 10-5M, p<0.001). ACh-induced vasorelaxation of isolated descending thoracic aortas from both high fat diet-induced obese wildtype mice and old-aged wildtype mice were significantly impaired, whereas these endothelial abnormalities were attenuated in Angptl2 knockout (KO) mice, respectively (49.59±3.73 vs. 71.43±3.09%, 58.27±5.14 vs. 89.52±2.85% relaxation at 10-5M, p<0.005). Next, to clarify the effect of Angptl2 deficiency on the progression of atherosclerosis, we generated Angptl2/ApoE double KO (DKO) mice. Atherosclerotic lesion in Angptl2/ApoE DKO mice was significantly reduced compared with ApoE KO mice (10.85±1.05 vs. 17.62±1.36%, p<0.005), whereas there was no difference in lipid metabolic characteristics between them. These results suggest that endothelial cells-derived Angptl2 is a key mediator that links vascular inflammation to endothelial dysfunction and atherosclerosis and that Angptl2 represents a novel target to antagonize these pathologies.
- © 2011 by American Heart Association, Inc.