title: Matrix metalloproteinase-2 proteolysis of calponin-1 contributes to vascular hypocontractility in endotoxemic rats.
abstract: OBJECTIVE
  Matrix metalloproteinase (MMP)-2 is activated in aorta during endotoxemia and plays a role in the hypocontractility to vasoconstrictors. Calponin-1 is a regulator of vascular smooth muscle tone with similarities to troponin, a cardiac myocyte protein that is cleaved by MMP-2 in myocardial oxidative stress injuries. We hypothesized that calponin-1 may be proteolyzed by MMP-2 in endotoxemia-induced vascular hypocontractility.
  
  
  RESULTS
  Rats were given a nonlethal dose of bacterial lipopolysaccharide (LPS) or vehicle. Some rats were given the MMP inhibitors ONO-4817 or doxycycline. Six hours later, plasma nitrate+nitrite increased >15-fold in LPS-treated rats, an effect unchanged by doxycycline. Both ONO-4817 and doxycycline prevented LPS-induced aortic hypocontractility to phenylephrine. LPS activated MMP-2 in the aorta by S-glutathiolation. Calponin-1 levels decreased by 25% in endotoxemic aortae, which was prevented by doxycycline. Calponin-1 and MMP-2 coimmunoprecipitated and both exhibited uniform cytosolic staining in medial vascular smooth muscle cells. In vitro incubation of calponin-1 with MMP-2 led to calponin-1 degradation and appearance of its cleavage product.
  
  
  CONCLUSIONS
  Calponin-1 is a target of MMP-2, which contributes to endotoxemia-induced vascular hypocontractility.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, 4-62 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Michele M
authors.initials: MM
authors.lastname: Castro
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cena
authors.forename: Woo Jung
authors.initials: WJ
authors.lastname: Cho
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D019446:Endotoxemia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology*; D005978:Glutathione / Q000378:metabolism; D047468:Immunoprecipitation; D008070:Lipopolysaccharides; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008840:Microfilament Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology*; D010647:Phenyl Ethers / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000096985:Calponins
chemical_list: D002135:Calcium-Binding Proteins; D004318:Doxycycline; D005978:Glutathione; D008070:Lipopolysaccharides; D020778:Matrix Metalloproteinase 2; D061965:Matrix Metalloproteinase Inhibitors; D008840:Microfilament Proteins; D010647:Phenyl Ethers; D011480:Protease Inhibitors; D014662:Vasoconstrictor Agents; D000096985:Calponins; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; C522363:Mmp2 protein, rat