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Nuclear matrix metalloproteinase-2 in the cardiomyocyte and the ischemic-reperfused heart

Sabina Baghirova1, Bryan G Hughes2, Mathieu Poirier2

  • 1Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.

Journal of Molecular and Cellular Cardiology
|April 16, 2016
PubMed

Insights

Matrix metalloproteinases (MMPs) increase in heart nuclei during oxidative stress. While MMP-2 targets nuclear proteins like lamin A in vitro, its nuclear function during myocardial ischemia-reperfusion injury remains unclear.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs) are crucial for extracellular matrix remodeling, particularly following cardiac oxidative stress.
  • MMP-2, a specific MMP, has been detected in the cell nucleus, but its precise nuclear roles are not well understood.
  • Nuclear structural proteins, such as lamins, are potential targets for MMP-2 activity during cellular stress.

Purpose of the Study:

  • To investigate the presence and activity of MMP-2 in the cardiomyocyte nucleus under normal and ischemia-reperfusion (I/R) injury conditions.
  • To determine if MMP-2 proteolyzes nuclear structural proteins, specifically lamins A and B, during myocardial I/R injury.
  • To assess the impact of MMP inhibition on nuclear MMP-2 activity and lamin integrity.

Main Methods:

  • In vitro digestion assays using purified MMP-2 and lamins A/B to assess cleavage.
  • Immunofluorescent confocal microscopy and subcellular fractionation to localize MMP-2 in cardiomyocytes.
  • Langendorff perfusion of rat hearts subjected to aerobic conditions or I/R injury, with and without an MMP inhibitor (o-phenanthroline).
  • Analysis of nuclear MMP-2 activity, protein levels of MMP-2, troponin I, lamin A, and lamin B in heart tissue.

Main Results:

  • MMP-2 proteolyzed lamin A into a ~50kDa fragment in vitro, a process predicted by in silico analysis.
  • MMP-2 was localized to both the cytosol and nuclei of neonatal rat ventricular myocytes.
  • Nuclear MMP-2 activity increased significantly in hearts subjected to I/R injury, although total protein levels did not change.
  • MMP inhibition effectively preserved troponin I levels in I/R hearts but did not alter lamin A or B levels.
  • Lamin A and B levels remained unchanged in I/R hearts, suggesting they are not significantly degraded by MMP-2 in vivo during this injury model.

Conclusions:

  • MMP-2 exhibits widespread subcellular distribution in cardiomyocytes, including a notable nuclear presence.
  • Increased nuclear MMP-2 activity during myocardial stunning suggests uncharacterized biological functions.
  • Further investigation is needed to elucidate the specific nuclear roles of MMP-2 during cardiac I/R injury, potentially requiring more severe ischemic conditions for observable lamin proteolysis.
Keywords:
LaminMatrix metalloproteinase-2Myocardial ischemiaNucleusProteolysisReperfusion

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