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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

French, Christopher J MD; Zaman, A.K.M Tarikuz MBBS; Sobel, Burton E MD

Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0b013e31821dcbea
Original Article
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.

Author Information

From the Department of Medicine, Cardiovascular Research Institute, University of Vermont, Burlington, VT.

Received for publication January 11, 2011; accepted April 3, 2011.

Supported by Takeda Pharmaceutical Company Limited. C.J. French was supported in part by a Hemostasis and Thrombosis Training Program, K.G. Mann T32, HL07594.

The authors declare no conflicts of interest.

Reprints: Christopher French, MD, Cardiovascular Research Institute, University of Vermont, Colchester Research Facility, 208 South Park Drive, Colchester 05446, VT (e-mail: christopher.french@uvm.edu).

Copyright © 2011 Wolters Kluwer Health, Inc. All rights reserved.