ALDOSE REDUCTASE INHIBITOR PREVENTS HYPERPROLIFERATION AND HYPERTROPHY OF CULTURED RAT VASCULAR SMOOTH-MUSCLE CELLS INDUCED BY HIGH GLUCOSE

Vascular remodeling is a key process in the pathophysiology of atheros clerosis. Recent evidence suggests that high glucose levels may functi on as a vascular smooth muscle growth and proliferation-promoting subs tance. To explore the role of the polyol pathway in this process, we e xamined the effect of an aldose reductase inhibitor (ARI), epalrestat, on the growth characteristics of cultured rat vascular smooth muscle cells (VSMCs). Epalrestat (10 nmol/L, 1 mu mol/L) significantly suppre ssed the high glucose-induced proliferative effect as measured by [H-3 ]thymidine incorporation by 67% and 82% in cell number, suggesting ARI as an antimitogenic factor. In VSMCs, epalrestat (10 nmol/L, 1 mu mol /L) significantly suppressed the high glucose-induced incorporation of [H-3]leucine by 45% and 55% with the concomitant reduction of the cel l size estimated by flowcytometry. Epalrestat (1 mu mol/L) also suppre ssed high glucose-induced intracellular NADH/NAD(+) increase and membr ane-bound protein kinase C activation. These results indicate that thi s ARI possesses an antiproliferative and antihypertrophic action on VS MCs induced by high glucose possibly through protein kinase C suppress ion.