Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice.

Abstract

Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice. ApoE-deficient mice were fed a high-fat diet (HFD) and angiotensin II (Ang II) was infused by osmotic minipumps from 10-week-old for 4weeks. AR-R17779 was given in drinking water ad libitum. Oil red O staining of the aorta showed that combined loading of HFD and Ang II induced marked atherosclerosis compared with control mice fed a normal chow. Treatment with AR-R17779 significantly reduced atherosclerotic plaque area and improved survival of mice. Treatment with AR-R17779 also suppressed abdominal aortic aneurysm formation. Quantitative RT-PCR of the aorta revealed that mRNA expression levels of interleukin-1β, interleukin-6 and NOX2 were significantly decreased in AR-R17779-treated mice compared with Ang II+HFD mice. AR-R17779 treatment also reduced blood pressure and serum lipid levels. In conclusion, α7nAChR activation attenuates atherogenesis and aortic abdominal aneurysm formation in ApoE-deficient mice possibly through an anti-inflammatory effect and reduction of blood pressure and lipid levels. Pharmacological activation of α7nAChR may have a therapeutic potential against atherosclerotic vascular diseases through multiple mechanisms.

• Authors: Toru Hashimoto, Toshihiro Ichiki, Aya Watanabe, Eva Hurt-Camejo, Erik Michaëlsson, Jiro Ikeda, Eriko Inoue, Hirohide Matsuura, Tomotake Tokunou, Shiro Kitamoto, Kenji Sunagawa
• Journal: Vascular pharmacology (Vascul Pharmacol) 2014 May-Jun Vol. 61 Issue 2-3 Pg. 49-55 ISSN: 1879-3649 [Electronic] United States
• PMID: 24685818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• AR-R 17779
• Anti-Inflammatory Agents
• Apolipoproteins E
• Bridged-Ring Compounds
• Lipids
• Spiro Compounds
• alpha7 Nicotinic Acetylcholine Receptor

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Aortic Aneurysm (prevention & control)
• Apolipoproteins E (genetics)
• Atherosclerosis (prevention & control)
• Blood Pressure (drug effects)
• Bridged-Ring Compounds (pharmacology)
• Disease Models, Animal
• Lipids (blood)
• Male
• Mice
• Mice, Knockout
• Rats
• Rats, Sprague-Dawley
• Spiro Compounds (pharmacology)
• alpha7 Nicotinic Acetylcholine Receptor (agonists, metabolism)