Activation of proMMP-2 by U46619 occurs via involvement of p 38MAPK-NFκB-MT1MMP signaling pathway in pulmonary artery smooth muscle cells

Animesh Chowdhury, Soumitra Roy, Tapati Chakraborti, Kuntal Dey, Sajal Chakraborti

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

We investigated the mechanism by which TxA2 mimetic, U46619, activates proMMP-2 in bovine pulmonary artery smooth muscle cells. Our study showed that treatment of the cells with U46619 caused an increase in the expression and subsequently activation of proMMP-2 in the cells. Pretreatment with p38MAPK inhibitor, SB203580; and NF-κB inhibitor, Bay11-7082 inhibited the expression and activation of proMMP-2 induced by U46619. U46619 also induced increase in MT1-MMP expression, which was inhibited upon pretreatment with SB203580 and Bay11-7082. U46619 treatment to the cells stimulated p38MAPK activity as well as NF-κB activation by IκB-α phosphorylation, translocation of NF-κBp65 subunit from cytosol to nucleus and subsequently, by increasing its DNA-binding activity. Induction of NF-κB activation seems to be mediated through IKK, as transfection of cells with either IKKα or IKKβ siRNA prevented U46619-induced phosphorylation of IκB-α and NF-κBp65 DNA-binding activity. U46619 treatment to the cells also downregulated the TIMP-2 level. Pretreatment of the cells with SB203580 and Bay11-7082 did not show any discernible change in TIMP-2 level by U46619. Overall, U46619-induced activation of proMMP-2 is mediated via involvement of p38MAPK- NFκB-MT1MMP signaling pathway with concomitant downregulation of TIMP-2 expression in bovine pulmonary artery smooth muscle cells.

Original languageEnglish
Pages (from-to)53-68
Number of pages16
JournalMolecular and Cellular Biochemistry
Volume385
Issue number1-2
DOIs
StatePublished - 1 Jan 2014
Externally publishedYes

Keywords

  • MT1-MMP
  • NF-κB
  • TIMP-2
  • pMAPK
  • proMMP-2

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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