title: 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.affiliation: Department of Medicine, Cardiovascular Research Institute, University of Vermont, Burlington, VT, USA. christopher.french@uvm.edu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: French
authors.forename: A K M Tarikuz
authors.initials: AK
authors.lastname: Zaman
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D012083:Renin / Q000097:blood
chemical_list: D057911:Angiotensin Receptor Antagonists; D001057:Apolipoproteins E; D001562:Benzimidazoles; D010069:Oxadiazoles; D017395:Plasminogen Activator Inhibitor 1; D012083:Renin; C557413:azilsartan medoxomil