Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice. Issue 2 (August 2015)

• Record Type: Journal Article
• Authors: Theelen, Thomas L.; Lappalainen, Jari P.; Sluimer, Judith C.; Gurzeler, Erika; Cleutjens, Jack P.; Gijbels, Marion J.; Biessen, Erik A.L.; Daemen, Mat J.A.P.; Alitalo, Kari; Ylä-Herttuala, Seppo
• Is Part Of: Atherosclerosis. Volume 241:Issue 2(2015)
• Page Start: 297
• Page End: 304
• Publication Date: 2015-08
• Subjects: Angiogenesis -- Microvascular leakage -- Plaque stability -- Angiopoietin-2 -- Atherosclerosis; Ang-1 angiopoietin-1 -- Ang-2 angiopoietin-2 -- ApoB apolipoprotein B -- LDLr low density lipoprotein receptor -- MMP matrix metalloproteinase -- VEGF-A vascular endothelial growth factor-A; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.05.018
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Objective: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Methods: Hypercholesterolemic (low-density lipoprotein receptor −/− apolipoprotein B 100/100 ) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4–8.To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Results: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (−72%, p < 0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (−27%, p < 0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. Conclusions: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice. Highlights: Antibody-mediated Ang-2 blockage delays fatty streak formation in mice. Ang-2 blockage lowers plasma triglyceride levels. Ang-2 blockage has no negative effects on preexisting atherosclerosis.