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Published on: September 26, 2018
Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice
Thomas L Theelen1, Jari P Lappalainen2, Judith C Sluimer1
1Department of Pathology, CARIM, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
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.
Insights
Blocking Angiopoietin-2 (Ang-2) reduced early atherosclerosis and triglycerides in mice. This approach did not negatively impact existing plaques, suggesting potential therapeutic benefits for atherosclerosis development.
Area of Science:
- Cardiovascular Research
- Immunology
- Molecular Biology
Background:
- Angiopoietin-2 (Ang-2) is implicated in atherosclerosis and plaque instability.
- Ang-2 blocking agents are in clinical trials for cancer, but their role in cardiovascular disease is less understood.
- Investigating Ang-2's role in atherogenesis is crucial for potential therapeutic strategies.
Purpose of the Study:
- To determine the role of Angiopoietin-2 (Ang-2) in the development of atherosclerosis.
- To evaluate the effect of antibody-mediated Ang-2 blockage on atherogenesis in a mouse model.
- To assess if Ang-2 blockage influences the transition from subclinical to clinically relevant atherosclerosis.
Main Methods:
- Hypercholesterolemic mice were fed a high-cholesterol diet for eight weeks.
- Ang-2 blocking antibody treatment was administered during weeks 4-8.
- Peri-adventitial collars were placed on carotid arteries to promote plaque development.
- Aortic root, carotid, and brachiocephalic arteries were analyzed for plaque size and characteristics.
Main Results:
- Anti-Ang-2 treatment significantly reduced fatty streak size in the brachiocephalic artery (-72%, p < 0.05).
- Plasma triglyceride levels were decreased by Ang-2 blockage (-27%, p < 0.05).
- No significant effect was observed on the size or composition of pre-existing plaques in the aortic root or carotid arteries.
Conclusions:
- Angiopoietin-2 (Ang-2) blockage demonstrates a beneficial effect by reducing early atherosclerotic lesion formation.
- The treatment also led to a reduction in plasma triglyceride levels.
- Importantly, Ang-2 blockage did not adversely affect established atherosclerotic plaques in this model.
