Pressure overload promotes HMGB1 signaling in the ischemic-reperfused heart

Damage-Associated Molecular Patterns (DAMPs) are released following tissue injury and can activate pro-inflammatory pathways. Prototypical DAMPs include the High-Mobility Group Box 1 (HMGB1) protein which is released from necrotic cells. In turn, HMGB1 promotes inflammation via mechanisms likely involving phosphorylation/ activation of c-Jun-NH2-Terminal Kinase (JNK) and production of the inflammasome-associated cytokine, interleukin-1β (IL-1β). We have shown that pressure overload increases infarct size in association with poorer functional recovery of the heart subjected to an ischemia-reperfusion insult. This study tested the hypothesis that pressure overload augments HMGB1 expression in association with increased IL-1β generation and JNK phosphorylation thereby contributing to increased tissue injury. 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 cm H₂O. Thereafter, hearts were processed for flow cytometry and Western blot studies. The ischemic-reperfused hearts subjected to the high pressure displayed (a) greater expression of HMGB1 and IL-1β which were shown to also be generated by cardiomyocytes, (b) increased phosphoJNK levels and c) increased necrotic and apoptotic cell death. Collectively, the results suggest that pressure-related upregulation of HMGB1 signaling contributes to the pro-inflammatory response of the ischemic-reperfused heart involving augmented JNK activation and IL-1β generation.