Zoledronate upregulates MMP-9 and -13 in rat vascular smooth muscle cells by inducing oxidative stress

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dc.contributor.authorArun M.Z.
dc.contributor.authorReel B.
dc.contributor.authorSala-Newby G.B.
dc.contributor.authorBond M.
dc.contributor.authorTsaousi A.
dc.contributor.authorMaskell P.
dc.contributor.authorNewby A.C.
dc.date.accessioned2019-10-27T08:20:37Z
dc.date.available2019-10-27T08:20:37Z
dc.date.issued2016
dc.departmentEge Üniversitesien_US
dc.description.abstractBackground: Bisphosphonates, including zoledronate, target osteoclasts and are widely used in the treatment of osteoporosis and other bone resorption diseases, despite side effects that include damaging the stomach epithelium. Beneficial and adverse effects on other organ systems, including the cardiovascular system, have also been described and could impact on the use of bisphosphonates as therapeutic agents. Vascular smooth muscle cells (VSMCs) are major constituents of the normal vascular wall and have a key role in intimal thickening and atherosclerosis, in part by secreting MMPs that remodel the extracellular matrix and cleave cell surface proteins or secreted mediators. In this study, we investigated the effects of zoledronate on MMP expression. Methods: Rat VSMCs were stimulated by PDGF (50 ng/mL) plus TNF-? (10 ng/mL) or left unstimulated for a further 24 hours in serum-free medium. In other series of experiments, cells were pre-treated either with SC-514 (50 µM) or with apocynin (20 nM) for 2 hours, then zoledronate (100 µM) was added into 2% fetal calf serum containing medium for 24 hours. Results and discussion: Using isolated rat VSMCs in culture, zoledronate (100 µM) increased MMP-9 and -13 mRNA expressions but inhibited MMP-2 expression. MMP-9 and MMP-13 up-regulation was shown to depend on the NF-?B pathway; and this was activated by zoledronate. Furthermore, zoledronate elevated the levels of reactive oxygen species detected by either dichlorofluorescein in isolated VSMCs or lucigenin enhanced chemiluminescence in rat aortic rings in vitro. Apocynin, an inhibitor of NADPH oxidase, reversed NF-?B activation and MMP-9 and MMP-13 up-regulation by zoledronate. Conclusion: We conclude that zoledronate increases MMP-9 and MMP-13 expressions in rat VSMCs dependent upon stimulation of the NF-?B pathway by reactive oxygen species. Effects on MMP expression may contribute to the pharmacologic profile of bisphosphonates. © 2016 Arun et al.en_US
dc.description.sponsorshipBritish Heart Foundation: CH95/001 University of Bristol Ege Üniversitesien_US
dc.description.sponsorshipThe authors would like to thank Dr Goksel Gokce, Ege University Faculty of Pharmacy and Dr Steve White, University of Bristol for valuable help and expertise on oxidative stress measurements. MZA would also like to thank Prof Levent Ustunes for kind help and encouragement. This study was supported by the British Heart Foundation grant CH95/001. --en_US
dc.identifier.doi10.2147/DDDT.S103124en_US
dc.identifier.endpage1460en_US
dc.identifier.issn1177-8881
dc.identifier.pmid27143852en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1453en_US
dc.identifier.urihttps://doi.org/10.2147/DDDT.S103124
dc.identifier.urihttps://hdl.handle.net/11454/25730
dc.identifier.volume10en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherDove Medical Press Ltd.en_US
dc.relation.ispartofDrug Design, Development and Therapyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBisphosphonateen_US
dc.subjectMatrix metalloproteinaseen_US
dc.subjectReactive oxygen speciesen_US
dc.subjectVascular smooth muscle cellen_US
dc.subjectZoledronateen_US
dc.titleZoledronate upregulates MMP-9 and -13 in rat vascular smooth muscle cells by inducing oxidative stressen_US
dc.typeArticleen_US

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