Lalsoacidipine modulates the secretion of matrix metalloproteinase-9 by human macrophages

Activated macrophages within the arterial wall secrete matrix-degrading met alloproteinases (MMPs) that weaken the atherosclerotic plaque and contribut e to its fissuration. Preclinical studies have shown that calcium antagonis ts may reduce atherogenesis in the arterial wall. In the present study we e valuated the effect of lacidipine on 92-kDa gelatinase B (MMP-9) expression in human macrophages in cultures. Cells were treated for 24 h with lacidip ine and the conditioned media were analyzed. Lacidipine (1-20 muM) signific antly reduced, in a dose-dependent manner, MMP-9 potential gelatinolytic ca pacity up to 50%. When MMP-9 expression was stimulated by treatment with ph orbol esters or tumor necrosis factor-alpha, lacidipine was able to inhibit this enhanced gelatinolytic capacity up to 50 and 60%, respectively. Weste rn blot analysis and enzyme-linked immunosorbent assay showed a reduction o f MMP-9 protein actually released by cells. The addition of lacidipine in t he incubation media determined no significant variation in Ca2+ concentrati on. The drug did not affect MMP-9 mRNA levels, but it effectively reduced t he amount of both active and total free MMP-9 secreted by human macrophages . Lacidipine reduced also the secretion of the tissue inhibitor of metallop roteinase-1 (TIMP-1); however we observed an overall reduction of the gelat inolytic activity of the cells. Finally, peritoneal macrophages, obtained f rom mice treated with lacidipine, showed a reduced secretion of MMP-9. Toge ther, our data indicate that lacidipine may potentially exert an antiathero sclerotic activity by modulating the secretion of MMP-9 by macrophages. Thi s, in addition to the previously demonstrated inhibition of cholesterol est erification, may contribute to increase plaque stability.