Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice.

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.

• Authors: Thomas L Theelen, Jari P Lappalainen, Judith C Sluimer, Erika Gurzeler, Jack P Cleutjens, Marion J Gijbels, Erik A L Biessen, Mat J A P Daemen, Kari Alitalo, Seppo Ylä-Herttuala
• Journal: Atherosclerosis (Atherosclerosis) Vol. 241 Issue 2 Pg. 297-304 (Aug 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 26062989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Chemical References

• Angiopoietin-2
• Antibodies
• Apolipoprotein B-100
• Cholesterol, Dietary
• Receptors, LDL
• Triglycerides

Topics

• Angiopoietin-2 (antagonists & inhibitors, immunology, metabolism)
• Animals
• Antibodies (pharmacology)
• Aorta (drug effects, metabolism, pathology)
• Aortic Diseases (blood, genetics, immunology, pathology, prevention & control)
• Apolipoprotein B-100 (deficiency, genetics)
• Atherosclerosis (blood, genetics, immunology, pathology, prevention & control)
• Brachiocephalic Trunk (drug effects, immunology, metabolism, pathology)
• Carotid Arteries (drug effects, metabolism, pathology)
• Carotid Artery Diseases (blood, genetics, immunology, pathology, prevention & control)
• Cholesterol, Dietary (blood)
• Disease Models, Animal
• Hypercholesterolemia (blood, complications, genetics)
• Male
• Mice, Knockout
• Plaque, Atherosclerotic
• Receptors, LDL (deficiency, genetics)
• Time Factors
• Triglycerides (blood)