SKP-450 inhibits migration and DNA synthesis stimulated by oxidized low density lipoprotein in smooth muscle cells

This study was carried out to examine the inhibitory effects of SKP-450 (2-[2 "(1 ",3 "-dioxolone)-2-methyl]-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1-benzopyran), a potassium channel opener, on the proliferation and migration stimulated by oxidized low density Lipoprotein (LDL) of cultured smooth muscle cells of Wistar Kyoto rat aorta. SKP-450 (10(-7) and 10(-6) M) as well as probucol (10(-7) - 10(-5) M) reduced the production of thiobarbituric acid reactive substances from LDL submitted to CuSO4 (10 mu M). The increased [H-3]thymidine incorporation and migration (chemotactic and wound-edge) of the cultured smooth muscle cells in association with increased production of platelet-derived growth factor (PDGF)-BB-like immunoreactivity stimulated by oxidized LDL were significantly reduced by SKP-450 (10(-7) - 10(-6) M). Inhibition by SKP-450 of the oxidized LDL-stimulated [H-3]thymidine incorporation was antagonized by iberiotoxin (10(-7) M), but not by glibenclamide (10(-6) M), suggestive of mediation of Ca2+-activated K+ channel opening in the action of SKP-450. Taken together, SKP-450 inhibited the proliferation and migration of the smooth muscle cells as well as PDGF production stimulated by oxidized LDL, accompanying with its antiperoxidative action. (C) 1999 Elsevier Science B.V. All rights reserved.