Abstract 13942: Vascular Tissue-derived Angiopoietin-like Protein2 Accelerates Atherosclerosis Through Increasing Vascular Inflammation
Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression, but molecular mechanisms underlying this activity remain unclear. Here, we show that angiopoietin-like protein 2 (Angptl2), a recently identified pro-inflammatory secreted factor, is overexpressed in vascular tissue from atherosclerotic apolipoprotein E knockout (ApoE-/-) mice and CVD patients. Histological analysis demonstrated that Angptl2 was abundantly expressed in atheromatous plaques, particularly in endothelial cells and infiltrated macrophages in both ApoE-/- mice and CVD patients. Angptl2 deficiency in ApoE-/- mice attenuated atherosclerosis severity. Conversely, ApoE-/- mice crossed with transgenic mice expressing Angptl2 driven by the endothelial cell/macrophage-specific Tie2 promoter (ApoE-/-/Tie2-Angptl2 Tg) showed exacerbated atherosclerosis severity, while Tie2-Angptl2 Tg mice alone did not develop atheromatous plaques. Tie2-Angptl2 Tg mice did, however, show endothelium-dependent vasodilatory dysfunction. Conversely, Angptl2 deficiency in mice attenuated the severity of endothelial dysfunction induced in the presence of hyperlipidemia or obesity. Angptl2 activated pro-inflammatory NF-κB signaling in vitro in endothelial cells, resulting in vascular inflammation. Finally, a prospective cohort study revealed that Framingham risk scores, the most common indicator of future events of coronary heart disease (CHD), the major common form of CVD, in the short term (<10 years), increased significantly with elevating quartiles of Angptl2 concentration, suggesting that circulating Angptl2 concentrations could predict future CHD development. Overall, our findings indicate that Angptl2-associated vascular inflammation accelerates atherosclerosis development. We propose that Angptl2 could serve as a target in novel prevention and treatment strategies for counteracting CVD.
- © 2013 by American Heart Association, Inc.