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Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2877-87. doi: 10.1161/ATVBAHA.113.302323. Epub 2013 Sep 26.

Hypoxia induces metalloproteinase-9 activation and human vascular smooth muscle cell migration through low-density lipoprotein receptor-related protein 1-mediated Pyk2 phosphorylation.

Author information

  • 1From the Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Barcelona, Spain (E.R.-L., J.C., L.N., L.B.); ICREC Research Program, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain (S.R., C.G.-M., A.B.-G.); and Cardiovascular Biochemistry Group, Biomedical Research Institute Sant Pau, IIB-Sant Pau, Barcelona, Spain (S.B.).

Abstract

OBJECTIVE:

Hypoxia disturbs vascular function by promoting extracellular matrix remodeling. Extracellular matrix integrity and composition are modulated by metalloproteinases (MMPs). Our aim was to investigate the role of low-density lipoprotein receptor-related protein 1 (LRP1) in regulating MMP-9/MMP-2 activation and vascular smooth muscle cells (VSMCs) migration in response to hypoxia, and to elucidate the LRP1-signaling pathways involved in this process.

APPROACH AND RESULTS:

Western blot analysis showed that hypoxia induced a sustained phosphorylation of proline-rich tyrosine kinase 2 concomitantly with LRP1 overexpression in human VSMCs (hVSMCs). Deletion of LRP1 using small-interfering RNA technology or treatment of hVSMCs with the Src family kinase inhibitor PP2 impaired hypoxia-induced phosphorylation of proline-rich tyrosine kinase 2 levels. Coimmunoprecipitation experiments showed that the higher amounts of phosphorylation of proline-rich tyrosine kinase 2/LRP1β immunoprecipitates in hypoxic hVSMCs were abolished in PP2-treated hVSMCs. Both LRP1 silencing and PP2 treatment were highly effective in the prevention of hypoxia-induced MMP-9 activation and hVSMC migration. Cellular subfractionation experiments revealed that PP2 effects may be caused by impairment of hypoxia-induced nuclear factor-κβ translocation to the nucleus. ELISA measurements showed that LRP1 silencing but not PP2 treatment increased interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1 secretion by hypoxic hVSMCs.

CONCLUSIONS:

Our findings determine a crucial role of LRP1-mediated Pyk2 phosphorylation on hypoxia-induced MMP-9 activation and hVSMC migration and therefore in hypoxia-induced vascular remodeling. Both LRP1 silencing and PP2 treatments also influence hypoxia-induced proinflammatory effects in hVSMCs. Therefore, further studies are required to establish therapeutical strategies that efficiently modulate vascular remodeling and inflammation associated with hypoxia-vascular diseases.

KEYWORDS:

LRP1 protein, human; hypoxia; matrix metalloproteinase 1; protein tyrosine kinase Pyk2

PMID:
24072693
[PubMed - indexed for MEDLINE]
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