Abstract 1709: Interstitial Endothelin Receptor Activation Contributes to Membrane Type-1 Matrix Metalloproteinase Activity During Ischemia and Reperfusion
Background: While the activation of matrix metalloproteinases (MMPs) has been implicated to contribute to transient left ventricular (LV) dysfunction with ischemia and reperfusion (IR), the specific subtypes and upstream pathways that evoke MMP activity remain unclear. Membrane type-1 MMP (MT1-MMP) is increased in human heart failure and contains promoter response elements to biological signals such as endothelin (ET), which is increased with IR. This study tested the hypothesis that interstitial ET receptor (ET-R) activation is a fundamental upstream event leading to local MT1-MMP activity with IR.
Methods/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 simultaneous measurement of interstitial MT1-MMP activity (validated and calibrated fluorogenic substrate) and ET (radioimmunoassay) in which one probe contained the ETA-R antagonist (BQ123, 1μM). LV stroke work fell from baseline with IR (45.1±3.5 vs 34.1±3.1 g·m, p<0.05). Interstitial ET levels were increased with IR consistent with heightened ETA-R activation (500±55%, p<0.05). Interstitial MT1-MMP activity was elevated with IR, which was blunted with local interstitial ET-R inhibition. (Figure⇓)
Conclusions: The unique findings of this study were two-fold. First, there was a local release of ET paralleled by increased MT1-MMP activity. Second, the ETA receptor subtype contributed to the induction of MT1-MMP activity. This is the first study to mechanistically demonstrate that the signaling cascade elicited by ET-R activation contributes to MT1-MMP activity in the context of IR.