Effects of dehydroepiandrosterone on mitogen-activated protein kinase in human aortic smooth muscle cells

The objective of the present study was to determine whether dehydroepiandro sterone (DHEA) modifies growth factor-induced mitogen-activated protein kin ase (MAPK) activation, based on our previous study demonstrating that DHEA attenuates fetal calf serum-induced proliferation in human male aortic smoo th muscle cells (human male aortic SMCs). Human male aortic SMCs were used for this study. platelet-derived growth factor-BE (PDGF-BB), epidermal, gro wth factor (EGF), and basic fibroblast growth factor (bFGF), but not insuli n-like growth factor-1 (IGF-1), stimulated MAPK activity. Only MAPK activat ion induced by PDGF-BB was reduced by pretreatment with DHEA, although DHEA did not affect the MAPK activation induced by EGF or bFGF. The basal and P DGF-stimulated MAPK activity were decreased by two types of cyclic AMP (cAM P) elevating agents and increased by cAMP-dependent protein kinase (PKA) in hibitor in human male aortic SMCs, suggesting that cAMP regulates MAPK nega tively. The intracellular cAMP was increased by PDGF-BB. The increase of cA MP by PDGF-BB was augmented by pretreatment with DHEA although DHEA alone d id not affect cAMP. Neither EGF nor bFGF affected cAMP with and without DHE A pretreatment. Secretion of PGE(2) induced by PDGF was augmented by pretre atment with DHEA. Stimulatory effects of DHEA on the production of PGE(2) a nd cAMP were partially canceled by aromatase inhibitor and completely cance led by indomethacin or selective inhibitor of cyclooxygenase-2. These resul ts suggest that DHEA inhibited MAPK activation induced by PDGF-BB via PGE(2 ) overproduction and subsequent cAMP-dependent pathway in human male aortic SMCs.