Elevated arginase I expression in rat aortic smooth muscle cells increasescell proliferation

Arginase, which exists as the isoforms arginase I and II, catalyzes the hyd rolysis of arginine to ornithine and urea. Ornithine is the principal precu rsor for production of polyamines, which are required for cell proliferatio n. Rat aortic smooth muscle cells (RASMC) contain constitutive arginase I, and arginase inhibitors cause inhibition of cell proliferation. The objecti ve of this study was to determine whether the elevated expression of argina se I in RASMC causes increased cell proliferation. RASMC were stably transf ected with either rat arginase I cDNA or a beta -galactosidasecantrol expre ssion plasmid. Western blots and arginase enzymatic assays revealed high-le vel expression of cytosolic arginase I in arginase I-transfected RASMC. Mor eover, this observation was associated with the increased production of ure a and polyamines and higher rates of RASMC proliferation. The two selective inhibitors of arginase, N-hydraxy-L-arginine and S-(2-baronoethyl)-Lcystei ne, inhibited arginase and decreased the production of urea and polyamines in arginase I-transfected RASMC, all of which were associated with the inhi bition of cell proliferation. This study demonstrates that elevated arginas e I expression increases RASMC proliferation by mechanisms involving increa sed production of polyamines. These observations suggest that arginase I pl ays a potentially important role in controlling RASMC proliferation.