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DJ Baltrukonis, S Kajiji, LF Nelms, MP Lawton, MD Aleo, ME Verdugo; Role of Small GTPases in Lovastatin and CJ-12,918-Induced Cataracts . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3542.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To investigate the role of small GTPases in lovastatin and CJ-12,918-induced cataracts. Methods: In vitro: Rat and canine lens epithelial cells (LEC) were treated with 10-50 µM lovastatin or CJ-12,918 (5-lipoxygenase inhibitor) for 48 hrs. RhoA/RhoB and Ras expression were analyzed in the membrane/cytosol fractions and phosphorylated ERK2 (P-ERK2) in the whole cell lysate by Western blot. In vivo: Sprague-Dawley rats were dosed daily with 200 mg/kg lovastatin or 250 mg/kg CJ-12,918 for 2 days. Lenses were harvested for analysis of cholesterol biosynthesis by [14C]acetate incorporation, gene expression profiling by Affymetrix GeneChip analysis, and Rho and Ras expression in the membrane/cytosol fractions by Western blot. Results: In vitro: In rat and canine LEC, lovastatin treatment decreased Ras and Rho expression in the membrane fraction with a concurrent increase in the cytosol fraction and decreased ERK2 phosphorylation in the whole cell lysates. No changes in rat or canine LEC isoprenylation patterns were observed with CJ-12,918 treatment while P-ERK2 decreased only in rat LEC. In vivo: Lovastatin treatment inhibited lenticular cholesterol biosynthesis (LCB) 72% on Day 1 with a return to baseline on day 2. Treatment with CJ-12,918 inhibited LCB 79% on Day 2. Rho and Ras expression as well as gene expression (day 2)(geranylgeranyl transferase, ERK1/2, Ras GAP, and Rho) were not altered by CJ-12,918 or lovastatin. Conclusion: CJ-12,918 does not appear to impair small GTPase isoprenylation in vitro or in vivo suggesting CJ-12,918 inhibits LCB below squalene in the sterol pathway. Our data supports lovastatin inhibition of small GTPase isoprenylation in rat and canine LEC in vitro but not in rat lenses in vivo. Further studies examining the role of small GTP binding proteins in lovastatin-induced canine cataracts are needed in order to support their role in lovastatin-induced cataract formation.
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