Cardiologia Clínica e Experimental
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Pressure Overload Promotes HMGB1 Signaling in the Ischemic-reperfused Heart

Babak Baban, Jun Yao Liu and Mahmood S Mozaffari

Damage-Associated Molecular Patterns (DAMPs) are released following tissue injury and can activate proinflammatory 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.