SELECTIVE INDUCTION OF HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTOR BY METHYLGLYOXAL AND 3-DEOXYGLUCOSONE IN RAT AORTIC SMOOTH-MUSCLE CELLS - THE INVOLVEMENT OF REACTIVE OXYGEN SPECIES FORMATION AND A POSSIBLE IMPLICATION FOR ATHEROGENESIS IN DIABETES

Methylglyoxal (MG) and 3-deoxyglucosone (3-DG), reactive dicarbonyl me tabolites in the glyoxalase system and glycation reaction, respectivel y, selectively induced heparin-binding epidermal growth factor (HB-EGF )-like growth factor mRNA in a dose- and time-dependent manner in rat aortic smooth muscle cells (RASMC). A nuclear run-on assay revealed th at the dicarbonyl may regulate expression of HB-EGF at the transcripti on level. The dicarbonyl also increased the secretion of HB-EGF from R ASMC. However, platelet-derived growth factor, another known growth fa ctor of smooth muscle cells (SMC), was not induced by both dicarbonyls . The dicarbonyl augmented intracellular peroxides prior to the induct ion of HB-EGF mRNA as judged by flow cytometric analysis using 2',7'-d ichlorofluorescin diacetate. N-acetyl-L-cysteine and aminoguanidine su ppressed both dicarbonyl-increased HB-EGF mRNA and intracellular perox ide levels in RASMC. DL-Buthionine-(S,R)-sulfoximine increased the lev els of 3-DG-induced HB-FGF mRNA. Furthermore, hydrogen peroxide alone also induced HB-EGF mRNA in RASMC. These results indicate that MG and 3-DG induce HB-EGF by increasing the intracellular peroxide levels. In addition, the pretreatment with 12-O-tetra-decanoylphorbol-13-acetate failed to alter dicarbonyl-induced HB-EGF mRNA expression in RASMC, s uggesting that the signal transducing mechanism is not mediated by pro tein kinase C. Since HB-EGF is known as a potent mitogen for smooth mu scle cells and is abundant in atherosclerotic plaques, the induction o f HB-EGF by MG and 3-DG, as well as the concomitant increment of intra cellular peroxides, may trigger atherogenesis during diabetes.