The objective of this study was to determine whether the
polyol pathway
enzyme aldose reductase mediates diabetes abnormalities in vascular smooth muscle cell (SMC) growth.
Aldose reductase inhibitors (
tolrestat or
sorbinil) or antisense
aldose reductase mRNA prevented hyperproliferation of cultured rat aortic SMCs induced by high
glucose. Cell cycle progression in the presence of high
glucose was blocked by
tolrestat, which induced a G0-G1 phase growth arrest. In situ, diabetes increased SMC growth and intimal
hyperplasia in balloon-injured carotid arteries of
streptozotocin-treated rats, when examined 7 or 14 days after injury. Treatment with
tolrestat (15 mg x kg(-1) x day(-1)) diminished intimal
hyperplasia and decreased SMC content of the lesion by 25%. Although
tolrestat treatment increased immunoreactivity of the lesion with
antibodies raised against
protein adducts of the lipid peroxidation product 4-hydroxy
trans-2-nonenal, no compensatory increase in lesion
fibrosis was observed. Collectively, these results suggest that inhibition of
aldose reductase prevents
glucose-induced stimulation of SMC growth in culture and in situ. Even though inhibition of
aldose reductase increases vascular oxidative stress, this approach may be useful in preventing abnormal SMC growth in vessels of diabetic patients.