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.


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 micromol/L), and lovastatin (5 to 20 micromol/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.
Luan
Zhaoxia
Z
Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
Chase
Alex J
AJ
Newby
Andrew C
AC
D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000633:toxicity; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003864:Depression, Chemical; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D012501:Saphenous Vein / Q000166:cytology; D019821:Simvastatin / Q000494:pharmacology*; D013185:Squalene / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D002791:Cholesterol, Dietary; D017077:Culture Media, Conditioned; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D013185:Squalene; D008148:Lovastatin; D019821:Simvastatin; C086276:cerivastatin; D045726:Metalloproteases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid