Abstract 442: Pressure Overload Promotes HMGB1-Inflammasome Signaling in the Ischemic-Reperfused Heart.
2012
Damage-associated molecular patterns (DAMPs) are released following tissue injury and cell death and can activate pro-inflammatory pathways. Prototypical DAMPs include the high-mobility group box 1 (HMGB1) protein which is released from necrotic cells. We have shown that pressure overload increases infarct size in association with poorer functional recovery of the heart subjected to an ischemia-reperfusion insult. In this study, we tested the hypothesis that pressure overload increases HMGB1 expression in association with increased pro-inflammatory changes and consequent cell death. Accordingly, hearts of male Sprague-Dawley rats were subjected to an ischemia (40 min) reperfusion (15 min) insult with perfusion pressure set at either 80 or 160 cmH 2 O. Thereafter, hearts were processed for flow cytometry-based, Western blotting and immunostaining studies. The ischemic-reperfused hearts subjected to the high pressure displayed greater expression of HMGB-1 in association with increased phosphorylation of c-jun-NH2-terminal kinase (JNK) and production of the inflammasome-associated cytokine, interleukin-1β. These changes were associated with greater disruption of mitochondrial membrane potential and increased apoptotic and necrotic cell death in hearts subjected to the high pressure. Collectively, the results suggest that pressure-related upregulation of HMGB1-inflammasome signaling contributes importantly to exacerbated cell death in the ischemic-reperfused heart.
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