Ischemia/reperfusion-induced myosin light chain 1 phosphorylation increases its degradation by matrix metalloproteinase 2

Virgilio J J Cadete, Jolanta Sawicka, Jagdip S. Jaswal, Gary D. Lopaschuk, Richard Schulz, Danuta Szczesna-Cordary, Grzegorz Sawicki

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Degradation of myosin light chain 1 (MLC1) by matrix metalloproteinase 2 (MMP-2) during myocardial ischemia ? reperfusion (I ? R) has been demonstrated. However, the exact mechanisms controlling this process remain unknown. I ?R increases the phosphorylation of MLC1, but the consequences of this modification are not known. We hypothesized that phosphorylation of MLC1 plays an important role in its degradation by MMP-2. To examine this, isolated perfused rat hearts were subjected to 20 min global ischemia followed by 30 min of aerobic reperfusion. I ?R increased phosphorylation of MLC1 (as measured by mass spectrometry). When hearts were subjected to I ?R in the presence of ML-7 (a myosin light-chain kinase inhibitor) or doxycycline (an MMP inhibitor), improved recovery of contractile function was observed compared to aerobic controls, and MLC1 was protected from degradation. Enzyme kinetic studies revealed an increased affinity of MMP-2 for the phosphorylated form of MLC1 compared to non-phosphorylated MLC1. We conclude that MLC1 phosphorylation is an important mechanism controlling the intracellular action of MMP-2 and promoting degradation of MLC1. These results further support previous findings implicating post-translational modifications of contractile proteins as a key factor in the pathology of cardiac dysfunction during and following ischemia.

Original languageEnglish
Pages (from-to)2444-2454
Number of pages11
JournalFEBS Journal
Volume279
Issue number13
DOIs
StatePublished - Jul 1 2012

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Keywords

  • Doxycycline
  • Ischemia/reperfusion
  • Matrix metalloproteinase
  • Myosin light chain
  • Phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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