Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells.
Secretion of matrix metalloproteinases (MMPs) by macrophages and smooth muscle cells (SMC) may impair atherosclerotic cap integrity leading to atherosclerosis complications. Selective estrogen receptor modulators (SERMs) have favourable impact on plasma lipid levels, but their role in the prevention of atherosclerosis still remains unclear. We investigated the effects of raloxifene, a second generation SERM, on MMP expression and activity in cultured macrophages and SMC, and in rabbit carotid lesions. Human monocyte-derived macrophages were isolated from blood of healthy donors. SMC were isolated from the intima-media layers of collared rabbit carotid arteries. Cells were incubated for 24h with increasing concentrations of raloxifene. Ovariectomized rabbits fed a 1% cholesterol-rich diet were subjected to pericarotid collar placement and treated with or without 10mgkg(-1)d(-1) raloxifene for 2 weeks. In macrophages, raloxifene treatment (0.1-10microM) significantly reduced MMP-9 gelatinolytic potential in a concentration-dependent manner, without affecting MMP-9 activation. This effect was estrogen receptor (ER)-dependent and due to the inhibition of MMP-9 promoter-driven transcription following an interaction with NF-kB pathway. Similarly, in cultured SMC, raloxifene inhibited up to 40% MMP-2 gelatinolytic activity. In vivo, raloxifene decreased the expression of MMP-2, MMP-3, and MMP-9 by intimal cells and the total gelatinolytic activity of collared carotids. These effects were accompanied by reduction of lesion size and inhibition of macrophage accumulation. Overall, results indicate that raloxifene may reduce MMPs expression and activity in macrophages and smooth muscle cells and favourably affect lesion formation.
Bellosta
Stefano
S
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Stefano.Bellosta@unimi.it
Baetta
Roberta
R
Canavesi
Monica
M
Comparato
Carmen
C
Granata
Agnese
A
Monetti
Mara
M
Cairoli
Fausto
F
Eberini
Ivano
I
Puglisi
Lina
L
Corsini
Alberto
A
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D016466:CHO Cells; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D002791:Cholesterol, Dietary; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D010052:Ovariectomy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D020849:Raloxifene Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D002791:Cholesterol, Dietary; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D011480:Protease Inhibitors; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9