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Increased Levels of Catalase and Cathepsin V/L2 but Decreased TIMP-1 in Keratoconus Corneas: Evidence that Oxidative Stress Plays a Role in This Disorder

2005; Cadmus Press; Volume: 46; Issue: 3 Linguagem: Inglês

10.1167/iovs.04-0549

1552-5783

M. Cristina Kenney, Marilyn Chwa, Shari R. Atilano, Annie Tran, Marilee Carballo, Mehrnoosh Saghizadeh, Vasilis Vasiliou, Wakako Adachi, Donald D. Brown,

Corneal Surgery and Treatments

The mRNA levels of antioxidant enzymes, matrix metalloproteinases, cathepsin V/L2, and tissue inhibitor of matrix metalloproteinases (TIMPs) were determined in keratoconus and normal corneas. Protein levels or enzyme activities were analyzed when RNA levels were different.A total of 25 physiologic (normal) and 32 keratoconus corneas were studied. mRNAs were analyzed by semiquantitative reverse transcription-polymerase chain reaction and Southern blot analysis. Proteins were assessed by immunohistochemistry and/or Western blot analysis. Catalase activity was measured in corneal extracts. Antioxidant enzymes examined were catalase, superoxide dismutase (SOD)-1, SOD3, glutathione reductase, glutathione S-transferase and aldehyde dehydrogenase 3A1. Degradative enzymes examined were cathepsin V/L2 and matrix metalloproteinase (MMP)-1, -2, -7, -9, and -14. Tissue inhibitor of matrix metalloproteinase (TIMP)-1, -2, and -3 were also examined.Keratoconus corneas exhibited a 2.2-fold increase of catalase mRNA level (P < 0.01) and 1.8-fold of enzyme activity (P < 0.03); a 1.5-fold increase of cathepsin V/L2 mRNA (P < 0.03) and abnormal protein distribution; and a 1.8-fold decrease of TIMP-1 mRNA (P < 0.05) and 2.8-fold decrease of protein (P < 0.0001) compared with normal (physiologic) corneas. RNA levels for other antioxidant and degradative enzymes were similar between normal and keratoconus corneas.Keratoconus corneas have elevated levels of cathepsins V/L2, -B, and -G, which can stimulate hydrogen peroxide production, which, in turn, can upregulate catalase, an antioxidant enzyme. In addition, decreased TIMP-1 and increased cathepsin V/L2 levels may play a role in the matrix degradation that is a hallmark of keratoconus corneas. The findings support the hypothesis that keratoconus corneas undergo oxidative stress and tissue degradation.