Abstract 230: Protein Kinase C is Requisite for Interstitial Membrane Type-1 Matrix Metalloproteinase Activity during Ischemia and Reperfusion
Background: Matrix metalloproteinases (MMPs), in particular membrane type-1 MMP (MT1-MMP), have been implicated to contribute to transient left ventricular (LV) dysfunction with ischemia and reperfusion (IR). However, the signaling pathways, which contribute to this process, remain unknown. Signaling molecules such as protein kinase C (PKC) contribute to formation of transcription factors that may regulate MT1-MMP transcription. This study tested the hypothesis that myocardial PKC activity is a fundamental requirement for MT1-MMP activation with IR in vivo.
Methods and Results: Pigs (30 kg, n=9) underwent IR (90 minutes of circumflex occlusion and 120 minutes of R) in which parallel microdialysis probes were placed in the LV IR area for measurement of interstitial MT1-MMP activity (calibrated fluorogenic substrate) in which one probe contained a PKC inhibitor (Chelerythrine, 1μM). LV stroke work fell from baseline with IR (45.1±3.5 vs 34.1±3.1 g·m, p<0.05). Interstitial MT1-MMP activity was elevated with IR and was attenuated with PKC inhibition (Figure⇓). PKC isoforms (immunoblotting) were measured and compared to normal myocardium (control, set at 100%, n=6). There was a 198±31% increase in PKC beta II protein while PKC epsilon was reduced (60±13%), indicative of differential activation (p<0.05 vs control).
Conclusions: This study, for the first time, demonstrated that PKC activity is requisite for the induction of MT1-MMP activity with IR and is likely regulated by specific isoforms. Strategies that target the signaling pathway elicited by PKC, or particular PKC isoforms may constitute a novel therapeutic target with respect to regulating MT1-MMP activity with IR.