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Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

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Abstract

Statins exert anti-inflammatory effects and downregulate matrix metalloproteinases (MMPs) expression, thus contributing to restore cardiovascular homeostasis in cardiovascular diseases. We aimed at comparing the effects of different statins (simvastatin, atorvastatin, and pravastatin) on MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios released by human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA). HUVECs were incubated with statins (0.1–10 μM) for 12 h before stimulation with PMA 100 nM. Monolayers were used to perform cell viability assays and the supernatants were collected to determine MMPs and TIMPs levels by gelatin zymography and/or enzyme immunoassay. While treatment with PMA increased MMP-9 and TIMP-1 levels (by 556% and 159%, respectively; both P < 0.05), it exerted no effects on MMP-2 and TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, attenuated PMA-induced increases in MMP-9 levels (P < 0.05). Only atorvastatin decreased baseline MMP-2 levels significantly (P < 0.05). We found no effects on TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, decreased MMP-9/TIMP-1 ratio significantly (both P < 0.05), whereas atorvastatin and pravastatin, but not simvastatin, decreased MMP-2/TIMP-2 ratio significantly (both P < 0.05). Our data support the notion that statins with different physicochemical features exert variable effects on MMP/TIMP ratios (which reflect net MMP activity). Our results suggest that more lipophilic statins (simvastatin and atorvastatin), but not the hydrophilic statin pravastatin, downregulate net MMP-9 activity. However, atorvastatin and pravastatin may downregulate net MMP-2 activity. The clinical implications of the present findings deserve further investigation.

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Acknowledgments

This study was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, SP, Brazil

    Tatiane C. Izidoro-Toledo, Danielle A. Guimaraes & Jose Eduardo Tanus-Santos

  2. Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil

    Vanessa A. Belo

  3. Department of Morphology, Stomatology and Physiology, Dental School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil

    Raquel F. Gerlach

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  1. Tatiane C. Izidoro-Toledo
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  3. Vanessa A. Belo
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  5. Jose Eduardo Tanus-Santos
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Correspondence to Jose Eduardo Tanus-Santos.

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Izidoro-Toledo, T.C., Guimaraes, D.A., Belo, V.A. et al. Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells. Naunyn-Schmiedeberg's Arch Pharmacol 383, 547–554 (2011). https://doi.org/10.1007/s00210-011-0623-0

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