title: Angiotensin inhibition decreases progression of advanced atherosclerosis and stabilizes established atherosclerotic plaques.
abstract: Although increased extracellular matrix (ECM) is pathogenic in a variety of chronic tissue injuries, reduced and/or disrupted ECM may be detrimental in atherosclerosis and rather destabilize existing atherosclerotic lesions. This study therefore assessed the effects of angiotensin II (AngII) antagonism on ECM components of advanced atherosclerosis. Twenty-four-week-old apolipoprotein E-deficient mice were treated with the AngII antagonist losartan for 12 wk. Controls received water or hydralazine. AngII antagonism significantly reduced progression of established atherosclerosis, whereas hydralazine showed no benefit despite similar decrease in BP. Although there was no difference in the macrophage component, AngII antagonism increased the relative collagen portion of the lesions; lessened elastin fragmentation, increased the total elastin content of the aorta; and reduced the mRNA and activity/protein of the elastolytic proteases, cathepsin S, and metalloproteinase-9. Extracellular elastin degradation by cultured smooth muscle cells (SMC) was reduced by losartan, as was SMC invasion through an elastin gel barrier. Thus, AngII antagonism lessens progression of atherosclerosis, increases collagen, and preserves elastin components of ECM within the vascular lesions, which, at least in part, is modulated by effects on SMC. These effects not only decrease further expansion of advanced lesions but also stabilize the established atherosclerotic plaques and may underlie the decreased incidence of acute cardiovascular events that are observed in patients in whom AngII antagonism is begun after atherosclerosis is already established.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232-2584, USA.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Suganuma
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: Masaru
authors.initials: M
authors.lastname: Motojima
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Zuo
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ayabe
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: Valentina
authors.initials: V
authors.lastname: Kon
mesh_terms: D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001018:Aortic Diseases / Q000188:drug therapy / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018450:Disease Progression; D004548:Elasticity; D005260:Female; D006830:Hydralazine / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D014662:Vasoconstrictor Agents / Q000097:blood / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D008055:Lipids; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D006830:Hydralazine; D019808:Losartan