title: Effects of rosuvastatin on the production and activation of matrix metalloproteinase-2 and migration of cultured rat vascular smooth muscle cells induced by homocysteine.
abstract: OBJECTIVE
  To test the influence of homocysteine on the production and activation of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) and on cell migration of cultured rat vascular smooth muscle cells (VSMCs). Also, to explore whether rosuvastatin can alter the abnormal secretion and activation of MMP-2 and TIMP-2 and migration of VSMCs induced by homocysteine.
  
  
  METHODS
  Rat VSMCs were incubated with different concentrations of homocysteine (50-5000 μmol/L). Western blotting and gelatin zymography were used to investigate the expressions and activities of MMP-2 and TIMP-2 in VSMCs in culture medium when induced with homocysteine for 24, 48, and 72 h. Transwell chambers were employed to test the migratory ability of VSMCs when incubated with homocysteine for 48 h. Different concentrations of rosuvastatin (10(-9)-10(-5) mol/L) were added when VSMCs were induced with 1000 μmol/L homocysteine. The expressions and activities of MMP-2 and TIMP-2 were examined after incubating for 24, 48, and 72 h, and the migration of VSMCs was also examined after incubating for 48 h.
  
  
  RESULTS
  Homocysteine (50-1000 μmol/L) increased the production and activation of MMP-2 and expression of TIMP-2 in a dose-dependent manner. However, when incubated with 5000 μmol/L homocysteine, the expression of MMP-2 was up-regulated, but its activity was down-regulated. Increased homocysteine-induced production and activation of MMP-2 were reduced by rosuvastatin in a dose-dependent manner whereas secretion of TIMP-2 was not significantly altered by rosuvastatin. Homocysteine (50-5000 μmol/L) stimulated the migration of VSMCs in a dose-dependent manner, but this effect was eliminated by rosuvastatin.
  
  
  CONCLUSIONS
  Homocysteine (50-1000 μmol/L) significantly increased the production and activation of MMP-2, the expression of TIMP-2, and the migration of VSMCs in a dose-dependent manner. Additional extracellular rosuvastatin can decrease the excessive expression and activation of MMP-2 and abnormal migration of VSMCs induced by homocysteine.
authors.affiliation: Department of Cardiology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing 312000, China.
authors.forename: Ya-fei
authors.initials: YF
authors.lastname: Shi
authors.forename: Ju-fang
authors.initials: JF
authors.lastname: Chi
authors.forename: Wei-liang
authors.initials: WL
authors.lastname: Tang
authors.forename: Fu-kang
authors.initials: FK
authors.lastname: Xu
authors.forename: Long-bin
authors.initials: LB
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ji
authors.forename: Hai-tao
authors.initials: HT
authors.lastname: Lv
authors.forename: Hang-yuan
authors.initials: HY
authors.lastname: Guo
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology*; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D006710:Homocysteine; D019716:Tissue Inhibitor of Metalloproteinase-2; D000068718:Rosuvastatin Calcium; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
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