EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-ΚB andMKK7/JNK/AP-1 signaling

Balachandar Venkatesan, Anthony J. Valente, Sumanth D. Prabhu, Prakashsrinivasan Shanmugam, Patrice Delafontaine, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

The transmembrane glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN), and the pleiotropic proinflammatory cytokine interleukin (IL)-18, play critical roles in myocardial remodeling, by inducing matrix degrading metalloproteinases (MMPs). Previously we showed that IL-18 induces EMMPRIN expression in cardiomyocytes via MyD88/IRAK4/TRAF6/JNK-dependent Sp1 activation. Here in reciprocal studies we demonstrate that EMMPRIN is a potent inducer of IL-18 transcription, protein expression and protein secretion in primary mouse cardiomyocytes. We show for the first time that EMMPRIN stimulates the activation of NF-ΚB, AP-1, CREB, and ATF-2 in cardiomyocytes, and induces IL-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-ΚB and MKK7/JNK/AP-1 signaling. Moreover, EMMPRIN induces robust time-dependent induction of various MMP mRNAs. EMMPRIN also induces the mRNA of TIMPs 1 and 3, but in a delayed fashion. These results suggest that IL-18-induced EMMPRIN expression may favor net MMP expression and ECM destruction, and thus identify both as potential therapeutic targets in countering adverse myocardial remodeling.

Original languageEnglish (US)
Pages (from-to)655-663
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume49
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • Cardiac hypertrophy
  • Matrix metalloproteinases
  • Myocardial failure
  • Myocardial remodeling
  • Proinflammatory cytokines

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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