Abstract 13980: Angiopoietin-Like Protein 2 is a Critical Inflammatory Mediator of Atherosclerosis
Chronic vascular inflammation plays crucial roles in pathogenesis of atherosclerosis, however the molecular mechanisms have not been fully clarified. We previously reported that angiopoietin-like protein 2 (Angptl2) was abundantly expressed in adipose tissue and that adipose tissue-derived Angptl2 promotes chronic adipose tissue inflammation and its-associated insulin resistance in obesity. Furthermore, we recently reported that circulating Angptl2 levels were significantly increased in patients with coronary artery disease. In the present study, we investigated whether Angptl2-induced inflammation in vascular walls contribute to progression of atheromatous plaques. To elucidate how Angptl2 accelerates atheromatous plaque progression, we prepared aortic lysates and serum obtained from ApoE knock out (KO) mice over time since atherosclerosis progresses with age in this model. The serum Angptl2 levels was elevated with increasing age/plaque burden. To determine which cell types express Angptl2 in atherosclerotic plaques, we performed immunofluorescence in the atherosclerotic aortic roots obtained from ApoE KO mice. Angptl2 were concurrently imaged with CD31 positive endothelial cells and CD68 positive macrophages in atheromatous plaques. Next, to clarify the effect of Angptl2 deficiency on the progression of atherosclerosis, we generated Angptl2/ApoE double KO (DKO) mice. Atherosclerotic lesion was significantly reduced in Angptl2/ApoE DKO mice 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 groups. In contrast, expression of E-selectin, VCAM-1, and ICAM-1 as makers of vascular inflammation, TNF-α, IL-6, and IL-1β as markers of general inflammation, and F4/80 and CD68 as indicators of macrophage accumulation was significantly decreased in vessels from Angptl2/ApoE DKO mice compared with ApoE single KO littermates. In conclusion, Angptl2 deficiency ameliorates the progression of atherosclerosis through suppressing vascular inflammation. These results suggest that Angptl2 may be a key mediator that links vascular inflammation to atherosclerosis and that Angptl2 represents a novel target to antagonize these pathologies.
- © 2012 by American Heart Association, Inc.