Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells

Stefano Bellosta, Roberta Baetta, Monica Canavesi, Carmen Comparato, Agnese Granata, Mara Monetti, Fausto Cairoli, Ivano Eberini, Lina Puglisi, Alberto Corsini

Research output: Contribution to journalArticle

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Abstract

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 24 h with increasing concentrations of raloxifene. Ovariectomized rabbits fed a 1% cholesterol-rich diet were subjected to pericarotid collar placement and treated with or without 10 mg kg-1 d-1 raloxifene for 2 weeks. In macrophages, raloxifene treatment (0.1-10 μM) 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.

Original languageEnglish
Pages (from-to)160-167
Number of pages8
JournalPharmacological Research
Volume56
Issue number2
DOIs
Publication statusPublished - Aug 2007

Fingerprint

Matrix Metalloproteinases
Smooth Muscle Myocytes
Macrophages
Matrix Metalloproteinase 9
Selective Estrogen Receptor Modulators
Matrix Metalloproteinase 2
Rabbits
Atherosclerosis
Tunica Intima
Matrix Metalloproteinase 3
NF-kappa B
Raloxifene Hydrochloride
Blood Donors
Carotid Arteries
Estrogen Receptors
Cholesterol
Diet
Lipids

Keywords

  • Macrophages
  • Metalloproteinase
  • Raloxifene
  • SERM
  • Smooth muscle cells

ASJC Scopus subject areas

  • Pharmacology

Cite this

Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells. / Bellosta, Stefano; Baetta, Roberta; Canavesi, Monica; Comparato, Carmen; Granata, Agnese; Monetti, Mara; Cairoli, Fausto; Eberini, Ivano; Puglisi, Lina; Corsini, Alberto.

In: Pharmacological Research, Vol. 56, No. 2, 08.2007, p. 160-167.

Research output: Contribution to journalArticle

Bellosta, S, Baetta, R, Canavesi, M, Comparato, C, Granata, A, Monetti, M, Cairoli, F, Eberini, I, Puglisi, L & Corsini, A 2007, 'Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells', Pharmacological Research, vol. 56, no. 2, pp. 160-167. https://doi.org/10.1016/j.phrs.2007.05.004
Bellosta, Stefano ; Baetta, Roberta ; Canavesi, Monica ; Comparato, Carmen ; Granata, Agnese ; Monetti, Mara ; Cairoli, Fausto ; Eberini, Ivano ; Puglisi, Lina ; Corsini, Alberto. / Raloxifene inhibits matrix metalloproteinases expression and activity in macrophages and smooth muscle cells. In: Pharmacological Research. 2007 ; Vol. 56, No. 2. pp. 160-167.
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abstract = "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 24 h with increasing concentrations of raloxifene. Ovariectomized rabbits fed a 1{\%} cholesterol-rich diet were subjected to pericarotid collar placement and treated with or without 10 mg kg-1 d-1 raloxifene for 2 weeks. In macrophages, raloxifene treatment (0.1-10 μM) 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.",
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AU - Granata, Agnese

AU - Monetti, Mara

AU - Cairoli, Fausto

AU - Eberini, Ivano

AU - Puglisi, Lina

AU - Corsini, Alberto

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