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

Virgilio J J Cadete1, Jolanta Sawicka, Jagdip S Jaswal

  • 1Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada.

The FEBS Journal
|May 9, 2012
PubMed

Insights

Myosin light chain 1 (MLC1) phosphorylation enhances its degradation by matrix metalloproteinase 2 (MMP-2) during heart ischemia/reperfusion (I/R). Inhibiting this process improves cardiac function and protects MLC1.

Area of Science:

  • Cardiovascular Biology
  • Enzymology
  • Molecular Cardiology

Background:

  • Myocardial ischemia/reperfusion (I/R) induces cardiac dysfunction.
  • Matrix metalloproteinase 2 (MMP-2) degrades myosin light chain 1 (MLC1) during I/R.
  • The role of MLC1 phosphorylation in MMP-2 mediated degradation is unclear.

Purpose of the Study:

  • To investigate the role of MLC1 phosphorylation in its degradation by MMP-2.
  • To determine if inhibiting MLC1 phosphorylation or MMP-2 activity improves cardiac function during I/R.

Main Methods:

  • Isolated perfused rat hearts subjected to ischemia/reperfusion (I/R).
  • Mass spectrometry to measure MLC1 phosphorylation.
  • Enzyme kinetic studies to assess MMP-2 affinity for phosphorylated MLC1.
  • Inhibition of myosin light-chain kinase (MLCK) with ML-7 and MMP with doxycycline.

Main Results:

  • I/R increased MLC1 phosphorylation.
  • MLCK inhibition (ML-7) or MMP inhibition (doxycycline) improved recovery of contractile function and protected MLC1 from degradation.
  • MMP-2 exhibited higher affinity for phosphorylated MLC1.

Conclusions:

  • MLC1 phosphorylation is a key mechanism controlling MMP-2 activity and promoting MLC1 degradation during I/R.
  • Targeting MLC1 phosphorylation or MMP-2 activity may offer therapeutic benefits for I/R injury.
  • Post-translational modifications of contractile proteins are critical in cardiac dysfunction following ischemia.

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