3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITORS INCREASE FIBRINOLYTIC-ACTIVITY IN RAT AORTIC ENDOTHELIAL-CELLS - ROLE OF GERANYLGERANYLATION AND RHO-PROTEINS

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ( HRIs) have been recently shown to prevent atherosclerosis progression. Clinical benefit results from combined actions on various components of the atherosclerotic lesion, This study was designed to identify the effects of HRI on one of these components, the endothelial fibrinolyt ic system. Aortas isolated from rats treated for 2 days with lovastati n (4 mg/kg body wt per day) showed a 3-fold increase in tissue plasmin ogen activator (tPA) activity. In a rat aortic endothelial cell line ( SVARECs) and in human nontransformed endothelial cells (HUVECs), HRI i nduced an increase in tPA activity and antigen in a time- and concentr ation-dependent manner. In SVARECs, the maximal response was observed when cells were incubated for 48 hours with 50 mu mol/L HRI. An increa se of tPA mRNA was also in evidence. In contrast, HRI inhibited plasmi nogen activator inhibitor-1 activity and mRNA. The effects of HRI were reversed by mevalonate and geranylgeranyl pyrophosphate, but not by L DL cholesterol and farnesyl pyrophosphate, and were not induced by alp ha-hydroxyfarnesyl phosphonic acid, an inhibitor of protein farnesyl t ransferase. C3 exoenzyme, an inhibitor of the geranylgeranylated-activ ated Rho protein, reproduced the effect of lovastatin on tPA and plasm inogen activator inhibitor-1 activity and blocked its reversal by gera nylgeranyl pyrophosphate. The effect of HRI was associated with a disr uption of cellular actin filaments without modification of microtubule s. A disrupter of actin filaments, cytochalasin D, induced the same ef fect as lovastatin on tPA, whereas a disrupter of microtubules, nocoda zole, did not. In conclusion, HRI can modify the fibrinolytic potentia l of endothelial cells, likely via inhibition of geranylgeranylated Rh o protein and disruption of the actin filaments. The resulting increas e of fibrinolytic activity of endothelial cells may contribute to the beneficial effects of HRI in the progression of atherosclerosis.