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

Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H875-83. doi: 10.1152/ajpheart.00918.2007. Epub 2007 Dec 7.


The matrix metalloproteinases (MMPs), in particular, membrane type 1 MMP (MT1-MMP), are increased in the context of myocardial ischemia and reperfusion (I/R) and likely contribute to myocardial dysfunction. One potential upstream induction mechanism for MT1-MMP is endothelin (ET) release and subsequent protein kinase C (PKC) activation. Modulation of ET and PKC signaling with respect to MT1-MMP activity with I/R has yet to be explored. Accordingly, this study examined in vivo MT1-MMP activation during I/R following modification of ET signaling and PKC activation. With the use of a novel fluorogenic microdialysis system, myocardial interstitial MT1-MMP activity was measured in pigs (30 kg; n = 9) during I/R (90 min I/120 min R). Local ET(A) receptor antagonism (BQ-123, 1 microM) and PKC inhibition (chelerythrine, 1 microM) were performed in parallel microdialysis probes. MT1-MMP activity was increased during I/R by 122 +/- 10% (P < 0.05) and was unchanged from baseline with ET antagonism and/or PKC inhibition. Selective PKC isoform induction occurred such that PKC-betaII increased by 198 +/- 31% (P < 0.05). MT1-MMP phosphothreonine, a putative PKC phosphorylation site, was increased by 121 +/- 8% (P < 0.05) in the I/R region. These studies demonstrate for the first time that increased interstitial MT1-MMP activity during I/R is a result of the ET/PKC pathway and may be due to enhanced phosphorylation of MT1-MMP. These findings identify multiple potential targets for modulating a local proteolytic pathway operative during I/R.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Endothelin B Receptor Antagonists
  • Endothelins / physiology*
  • Fluorescent Dyes
  • Immunoprecipitation
  • Isoenzymes / metabolism
  • Matrix Metalloproteinase 14 / metabolism*
  • Microdialysis
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / physiopathology*
  • Peptides, Cyclic / pharmacology
  • Phosphorylation
  • Protein Kinase C / metabolism
  • Receptor, Endothelin B / metabolism
  • Signal Transduction / physiology*
  • Stroke Volume / physiology
  • Swine
  • Threonine / metabolism


  • Endothelin B Receptor Antagonists
  • Endothelins
  • Fluorescent Dyes
  • Isoenzymes
  • Peptides, Cyclic
  • Receptor, Endothelin B
  • Threonine
  • Protein Kinase C
  • Matrix Metalloproteinase 14
  • cyclo(Trp-Asp-Pro-Val-Leu)