SPECIFIC-INHIBITION OF EIF-5A AND COLLAGEN HYDROXYLATION BY A SINGLE-AGENT - ANTIPROLIFERATIVE AND FIBROSUPPRESSIVE EFFECTS ON SMOOTH-MUSCLE CELLS FROM HUMAN CORONARY-ARTERIES

Restenosis occurs in 35% of patients within months after balloon angio plasty, due to a fibroproliferative response to vascular injury. These studies describe a combined fibrosuppressive/antiproliferative strate gy on smooth muscle cells cultured from human primary atherosclerotic and restenotic coronary arteries and from normal rat aortas. L-Mimosin e suppressed the posttranslational hydroxylation of the precursors for collagen and for eukaryotic initiation factor-5A (eIF-5A) by directly inhibiting the specific protein hydroxylases involved,prolyl 4-hydrox ylase (E.C. 1.14.11.2) and deoxyhypusyl hydroxylase (E.C. 1.14.99.29), respectively. Inhibition of deoxyhypusyl hydroxylation correlated wit h a dose-dependent inhibition of DNA synthesis. Inhibition of prolyl h ydroxylation caused a dose-dependent reduction in the secretion of hyd roxyproline-containing protein and decreased the formation of procolla gen types I and III. The antifibroproliferative action could not be at tributed to nonspecific or toxic effects of mimosine, appeared to be s elective for the hydroxylation step in the biosynthesis of the procoll agens and of eIF-5A, and was reversible upon removal of the compound. The strategy of targeting these two protein hydroxylases has important implications for the pathophysiology of restenosis and for the develo pment of agents to control fibroproliferative diseases.