CYSTEINYL LEUKOTRIENE D-4 INDUCED VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION - A POSSIBLE ROLE IN MYOINTIMAL HYPERPLASIA

Cysteinyl leukotrienes (i.e. LTC(4), LTD(4)), produced by activated le ukocytes or by transcellular metabolism may act at different levels on vascular smooth muscle cells (VSMC) during inflammatory processes or atherosclerosis. We studied the effect of LTC(4), LTD(4), and LTE(4) o n the in vitro proliferation of rat VSMC, measured by [H-3]-thymidine incorporation and cell count. LTD(4) had a stronger stimulatory effect on [H-3]-thymidine incorporation than LTC(4), whereas LTE(4) was inac tive. The effect of LTD(4) on [H-3]-thymidine incorporation was dose-d ependent, with the maximal activity at 10(-6) M. The stimulatory activ ity of LTD(4) was inhibited in a dose-dependent manner by MK-571, a sp ecific LTD(4) receptor antagonist. In addition, MK-571 (1 mg/kg/day) g iven for at least 1 day after injury in a model of balloon catheter in jury of rat carotid artery, provided effective inhibition of myointima l VSMC proliferation, with a 58% reduction of 5-bromo-2'-deoxyuridine (BrdU) uptake in the neointima and 69% reduction of neointimal thicken ing. Our data support the importance of inflammatory mechanisms in the pathogenesis of atherosclerosis and suggest a possible role for cyste inyl leukotrienes, specifically LTD(4), in the control of VSMC prolife ration.