Diltiazem, a calcium antagonist, inhibits matrix metalloproteinase-1 (tissue collagenase) production and collagenolytic activity in human vascular smooth muscle cells

Citation
Y. Wada et al., Diltiazem, a calcium antagonist, inhibits matrix metalloproteinase-1 (tissue collagenase) production and collagenolytic activity in human vascular smooth muscle cells, INT J MOL M, 8(5), 2001, pp. 561-566
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
ISSN journal
1107-3756 → ACNP
Volume
8
Issue
5
Year of publication
2001
Pages
561 - 566
Database
ISI
SICI code
1107-3756(200111)8:5<561:DACAIM>2.0.ZU;2-E
Abstract
Calcium antagonists (CAs) are widely prescribed for patients with cardiovas cular diseases. CAs have been reported to inhibit smooth muscle cell (SMC) proliferation in addition to their effects on vascular tone. To determine w hether CAs potentially affect vascular remodeling, we measured the expressi on of matrix-degrading, enzymes in growth factor-stimulated SMC. Human cult ured SMC were stimulated with 10 ng/ml of platelet-derived growth factor (P DGF)-BB with or without a calcium antagonist, diltiazem. In the cell counti ng assay, diltiazem (10(-5) M) alone had no effect on the proliferation of quiescent SMC, however 10(-6)-10(-5) M of diltiazem dose-dependently inhibi ted PDGF-stimulated SMC proliferation. The inhibitory effects of diltiazem on SMC proliferation were further confirmed by a 5-bromo-2'-deoxyuridine (B rdU) incorporation assay and flow cytometry. In Western blotting, matrix me talloproteinase (MMP)-1 (tissue collagenase) but not MMP-2 (72-kDa gelatina se) expression was upregulated by PDGF and phorbol ester (TPA), which were reduced by diltiazem in a dose-dependent manner. The downregulation of MMP- 1 expression was consistent with the reduction of collagenolytic activity m easured by a FITC-conjugated type I collagen breakdown assay. PDGF-stimulat ed c-Jun/AP-1 expression, a major transcriptional factor for MMP-1, was not affected by diltiazem. In contrast, intracellular calcium ions measured wi th a fluorometric assay of Fluo-3AM-loaded cells revealed that the PDGF-sti mulated increase in the intracellular calcium content was dose-dependently reduced by diltiazem. Our data suggest that diltiazem inhibits not only pro liferation but also MMP-1 expression and collagenolytic activity in PDGF-st imulated SMC. The administration of CAs potentially influences the process of vascular remodeling, and this possibility should be further verified in vivo.