Statins inhibit secretion of metalloproteinases-1,-2,-3, and-9 from vascular smooth muscle cells and macrophages

Objective - Production of several metalloproteinases ( MMPs) from smooth muscle cells (SMCs) and macrophages causes matrix destruction and atherosclerotic plaque instability. Statins, which inhibit HMG-CoA reductase and hence cholesterol and isoprenoid synthesis, stabilize plaques. We investigated whether statins inhibit MMP secretion from SMCs and macrophages. Methods and Results - We used human saphenous vein and rabbit aortic SMC and foamy macrophages from cholesterol-fed rabbits. Cerivastatin (50 nmol/L) inhibited inducible MMP-1, - 3, and - 9 secretion from human SMC by 52 +/- 19%, 71 +/- 18%, and 73 +/- 17%, respectively (P < 0.01, n = 3). Similar dose-related effects of cerivastatin ( 50 to 500 nmol/L), simvastatin (1 to 20 mu mol/L), and lovastatin (5 to 20 mu mol/L) were consistent with their relative potencies against HMG-CoA reductase. Statins also inhibited inducible MMP-1, - 3, and - 9 and constitutive MMP-2 secretion but not TIMP-1 or - 2 secretion from rabbit SMC. Statins also dose-dependently inhibited MMP-1, - 3, and - 9 secretion from rabbit foam cells; cerivastatin (50 nmol/L) inhibited by 68 +/- 18%, 74 +/- 14%, and 74 +/- 14%, respectively (P < 0.01, n = 4). Statins similarly decreased collagenolytic, caseinolytic, and gelatinolytic activity. Mevalonate and geranylgeranylpyrophosphate but not squalene reversed the effects, showing dependence on isoprenoid, not cholesterol depletion. Statins did not affect MMP mRNA levels. Conclusions - Statins inhibit secretion of a several MMPs from both SMCs and macrophages, which could therefore contribute to their plaque-stabilizing effects.