title: Role of the angiotensin converting enzyme 1/angiotensin II/angiotensin receptor 1 axis in interstitial collagenase expression in human carotid atheroma.
abstract: OBJECTIVE
  Angiotensin II (AII) receptor 1 (ATR1) and angiotensin converting enzyme 1 (ACE1) blockers have been shown to reduce acute cardiovascular events in patients, improve plaque stability and modify matrix metalloproteinase (MMP) expression. However, the role of the ACE1/AII/ATR1 axis in interstitial collagenase regulation has not been fully explored. In this study, we investigated the effect of ATR1 and ACE1 blockade on the expression and activity of MMP-1, -8 and -13 in human carotid atheroma.
  
  
  METHODS
  Atheroma samples (n = 24) were obtained from patients undergoing carotid endarterectomy. The effects of ATR1 (irbesartan), ACE1 (quinapril), ACE2 (DX600) and MMP (GM6001) blockade on the expression of AII, the interstitial collagenases and soluble elastin fragments were investigated in explant culture supernatants. Paired atheroma samples were incubated with intervention or media control for 4 days. Protein levels (AII, MMP-1, -8, -13 and soluble elastin) were determined by ELISA.
  
  
  RESULTS
  ATR1, but not ACE1, blockade significantly reduced MMP-1 and -8 concentrations in atheroma supernatants. ACE2 blockade significantly increased MMP-1 and -8 concentrations in atheroma supernatants. AII concentration in atheroma supernatants significantly increased after ATR1, ACE1 and ACE2 blockade. Release of soluble elastin fragments increased after ATR1 and ACE1 blockade, but was not changed by an MMP inhibitor.
  
  
  CONCLUSIONS
  Our findings suggest that ATR1 blockade alters AII, MMP-1, MMP-8 expression and a marker of elastin degradation in human atheroma, but that the elastin degradation response is not MMP driven. This data contributes to the recognised ability of ATR1 blockade to modify plaque stability.
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia. paula.clancy@jcu.edu.au
authors.forename: Paula
authors.initials: P
authors.lastname: Clancy
authors.forename: Sai-Wang
authors.initials: SW
authors.lastname: Seto
authors.forename: Simon A
authors.initials: SA
authors.lastname: Koblar
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017364:Collagenases / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D004549:Elastin / Q000378:metabolism; D016894:Endarterectomy, Carotid; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000077405:Irbesartan; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000077583:Quinapril; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; C556151:DX600 peptide; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles; D000804:Angiotensin II; D004549:Elastin; D007703:Peptidyl-Dipeptidase A; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D000077405:Irbesartan; D000077583:Quinapril
keywords: Angiotensin II; Angiotensin converting enzyme; Angiotensin receptor type 1; Atheroma; Elastin; Interstitial collagenase; Matrix metalloproteinase