Involvement of aldose reductase in vascular smooth muscle cell growth and lesion formation after arterial injury

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is an import ant feature of atherosclerosis, restenosis, and hypertension. Although mult iple mediators of VSMC growth have been identified, few effective pharmacol ogical tools have been developed to limit such growth. Recent evidence indi cating an important role for oxidative stress in cell growth led us to inve stigate the potential role of aldose reductase (AR) in the proliferation of VSMCs, Because AR catalyzes the reduction of mitogenic aldehydes derived f rom lipid peroxidation, we hypothesized that it might he a potential regula tor of redox changes that accompany VSMC growth. Herein we report several l ines of evidence suggesting that AR facilitates/mediates VSMC growth. Stimu lation of human aortic SMCs in culture with mitogenic concentrations of ser um, thrombin, basic fibroblast growth factor, and the lipid peroxidation pr oduct 4-hydroxy-trans-2-nonenal (HNE) led to a 2- to 4-fold increase in the steady-state levels of AR mRNA, a 4- to 7-fold increase in AR protein, and a 2- to 3-fold increase in its catalytic activity. Inhibition of the enzym e by sorbinil or tolrestat diminished mitogen-induced DNA synthesis and cel l proliferation. In parallel experiments, the extent of reduction of the gl utathione conjugate of HNE to glutathionyl-1,4-dihydroxynonene in HNE-expos ed VSMCs was decreased by serum starvation or sorbinil. Immunohistochemical staining of cross sections from balloon-injured rat carotid arteries showe d increased expression of AR protein associated with the neointima. The med ia of injured or uninjured arteries demonstrated no significant staining. C ompared with untreated animals, rats fed sorbinil (40 mg(.)kg(-1.)d(-1)) di splayed a 51% and a 58% reduction in the ratio of neointima to the media at 10 and 21 days, respectively, after balloon injury. Taken together, these findings suggest that AR is upregulated during growth and that this upregul ation facilitates growth by enhancing the metabolism of secondary products of reactive oxygen species.