The angiotensin receptor blocker, azilsartan medoxomil (TAK-491), suppresses vascular wall expression of plasminogen activator inhibitor type-I protein potentially facilitating the stabilization of atherosclerotic plaques.

Abstract

Increased expression of plasminogen activator inhibitor type-I (PAI-1) in vessel walls seems to accelerate atherosclerosis. Angiotensin II can increase the synthesis of PAI-1. Inhibition of this process may facilitate migration of vascular smooth muscle cells (VSMCs) stabilizing atherosclerotic plaques. To determine whether the inhibition of the angiotensin II type 1 receptor can blunt the expression of PAI-1 protein in the aortic wall, we administered azilsartan medoxomil (AZL-M), a prodrug of an angiotensin II type 1 receptor blocker developed by the Takeda Pharmaceutical Company Limited, for 16 weeks to ApoE knockout mice on a high fat diet rendered overexpressors of PAI-1 in VSMCs. Homogenates of the pooled aortas from each group were assayed for PAI-1 by enzyme-linked immunosorbent assay. Cellularity of atherosclerotic lesions was assessed by 4',6-diamidino-2-phenylindole staining in sections of aortic lesions, and collagen content in the lesions was quantified by immunohistochemistry. Aortic wall PAI-1 was decreased by each of the 3 dosage regimens of AZL-M (0.1-10 mg/kg). Cellularity and collagen were increased in lesions from mice given AZL-M, consistent with the development of more stable plaques. Accordingly, the suppression of PAI-1 expression by AZL-M may attenuate the evolution of atherosclerotic plaques vulnerable to rupture.

• Authors: Christopher J French, A K M Tarikuz Zaman, Burton E Sobel
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 58 Issue 2 Pg. 143-8 (Aug 2011) ISSN: 1533-4023 [Electronic] United States
• PMID: 21558880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Apolipoproteins E
• Benzimidazoles
• Oxadiazoles
• Plasminogen Activator Inhibitor 1
• Renin
• azilsartan medoxomil

Topics

• Angiotensin Receptor Antagonists (pharmacology, therapeutic use)
• Animals
• Aorta (drug effects, metabolism)
• Apolipoproteins E (genetics)
• Benzimidazoles (pharmacology, therapeutic use)
• Blood Pressure (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout
• Oxadiazoles (pharmacology, therapeutic use)
• Plaque, Atherosclerotic (blood, drug therapy, metabolism)
• Plasminogen Activator Inhibitor 1 (blood, genetics)
• Renin (blood)