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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H875    most recent 00918.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Deschamps, A. M. Articles by Spinale, F. G. Search for Related Content PubMed PubMed Citation Articles by Deschamps, A. M. Articles by Spinale, F. G.

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

¹Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston; and ²The Ralph H. Johnson Veteran's Affairs Medical Center, Charleston, South Carolina

Submitted 7 August 2007 ; accepted in final form 4 December 2007

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 µM) and PKC inhibition (chelerythrine, 1 µM) 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-βII 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.

myocardial interstitium; microdialysis; protein kinase C; phosphorylation; ischemia-reperfusion

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