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Interruption of endothelin signaling modifies membrane type 1 matrix metalloproteinase activity during ischemia and

Anne M Deschamps1, Juozas Zavadzkas, Rebecca L Murphy

  • 1Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29403, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|December 11, 2007
PubMed

Insights

Myocardial ischemia and reperfusion (I/R) increases matrix metalloproteinases (MMPs), specifically membrane type 1 MMP (MT1-MMP). This study shows the endothelin (ET)/protein kinase C (PKC) pathway drives MT1-MMP activation during I/R.

Area of Science:

  • Cardiovascular Biology
  • Proteolytic Pathways
  • Molecular Medicine

Background:

  • Matrix metalloproteinases (MMPs), particularly membrane type 1 MMP (MT1-MMP), are implicated in myocardial dysfunction following ischemia and reperfusion (I/R).
  • Endothelin (ET) release and protein kinase C (PKC) activation are potential upstream regulators of MT1-MMP, but their role in I/R-induced MT1-MMP activity is unexplored.

Purpose of the Study:

  • To investigate the in vivo role of the ET/PKC pathway in modulating MT1-MMP activity during myocardial I/R.
  • To identify potential therapeutic targets within this pathway for managing I/R-related cardiac injury.

Main Methods:

  • Utilized a novel fluorogenic microdialysis system in pigs to measure myocardial interstitial MT1-MMP activity during a 90-minute ischemia/120-minute reperfusion protocol.
  • Administered local ET(A) receptor antagonism (BQ-123) and PKC inhibition (chelerythrine) via microdialysis probes.
  • Assessed changes in MT1-MMP activity, PKC isoform expression (specifically PKC-betaII), and MT1-MMP phosphorylation at a putative PKC site.

Main Results:

  • Myocardial I/R significantly increased interstitial MT1-MMP activity by 122% (P < 0.05).
  • ET antagonism and/or PKC inhibition prevented the I/R-induced increase in MT1-MMP activity.
  • PKC-betaII expression increased by 198% (P < 0.05) and MT1-MMP phosphothreonine levels rose by 121% (P < 0.05) during I/R, suggesting PKC-mediated phosphorylation.

Conclusions:

  • The ET/PKC signaling pathway is a critical upstream regulator of interstitial MT1-MMP activation during myocardial I/R.
  • Enhanced MT1-MMP activity during I/R is likely mediated by PKC-dependent phosphorylation.
  • Targeting the ET/PKC pathway offers a potential therapeutic strategy to modulate proteolytic activity and mitigate cardiac damage in I/R injury.

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