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N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1β-mediated matrix metalloproteinase activation in cardiac fibroblasts

  • Signaling and Cell Physiology
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Myocardial matrix turnover involves a dynamic balance between collagen synthesis and degradation, which is regulated by matrix metalloproteinases (MMPs). N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) is a small peptide that inhibits cardiac inflammation and fibrosis. However, its role in MMP regulation is not known. Thus, we hypothesized that Ac-SDKP promotes MMP activation in cardiac fibroblasts and decreases collagen deposition via this mechanism. To that end, we tested the effects of Ac-SDKP on interleukin-1β (IL-1β; 5 ng/ml)-stimulated adult rat cardiac fibroblasts. We measured total collagenase activity, MMP-2, MMP-9, and MMP-13 expressions, and activity along with their inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. In order to examine the effects of Ac-SDKP on the signaling pathway that controls MMP transcription, we also measured nuclear factor-κB (NFκB) and p42/44 mitogen-activated protein kinase (MAPK) activation. Ac-SDKP did not alter collagenase or gelatinase activity in cardiac fibroblasts under basal conditions, but blunted the IL-1β-induced increase in total collagenase activity. Similarly, Ac-SDKP normalized the IL-1β-mediated increase in MMP-2 and MMP-9 activities and MMP-13 expression. Inhibition of MMPs by Ac-SDKP was associated with increased TIMP-1 and TIMP-2 expressions. Collagen production was not affected by Ac-SDKP, IL-1β, or a combination of both agents. Ac-SDKP blocked IL-1β-induced p42/44 phosphorylation and NFκB activation in cardiac fibroblasts. We concluded that the Ac-SDKP-inhibited collagenase expression and activation was associated with increased expression of TIMP-1 and TIMP-2. These pharmacological effects of Ac-SDKP may be linked to the inhibition of MAPK and NFκB pathway.

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Acknowledgments

This work was supported by National Institutes of Health grants HL-28982 (OAC) and HL-071806 (NER).

Conflict of interest

Nour-Eddine Rhaleb and Oscar A. Carretero received grant support from F. Hoffman-La Roche Ltd., Basel, Switzerland.

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Authors and Affiliations

  1. Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, E&R 7121, 2799 West Grand Boulevard, Detroit, MI, 48202, USA

    Nour-Eddine Rhaleb, Saraswati Pokharel, Umesh C. Sharma, Hongmei Peng, Pamela Harding, Xiao-Ping Yang & Oscar A. Carretero

  2. Department of Biostatistics, Henry Ford Hospital, Detroit, MI, USA

    Edward Peterson

  3. Department of Physiology, Wayne State University, Detroit, MI, USA

    Nour-Eddine Rhaleb

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  1. Nour-Eddine Rhaleb
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  2. Saraswati Pokharel
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Correspondence to Nour-Eddine Rhaleb.

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Drs. Rhaleb and Pokharel are co-first authors.

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Rhaleb, NE., Pokharel, S., Sharma, U.C. et al. N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1β-mediated matrix metalloproteinase activation in cardiac fibroblasts. Pflugers Arch - Eur J Physiol 465, 1487–1495 (2013). https://doi.org/10.1007/s00424-013-1262-8

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  • DOI: https://doi.org/10.1007/s00424-013-1262-8

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