Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4

Abstract While cardiac functional recovery is attenuated in the elderly following cardiac surgery with obligatory global myocardial ischemia/reperfusion (I/R), the underlying mechanism remains incompletely understood. We observed previously that human and mouse myocardium releases heat shock protein (HSP) 27 during global I/R. Extracellular HSP27 induces myocardial inflammatory response and plays a role in postischemic cardiac dysfunction in adult mouse hearts. This study was to determine the role of extracellular HSP27 and Toll-like receptor 4 (TLR4) in the attenuated functional recovery in aging mouse hearts following global I/R. Hearts isolated from aging (18–24 months) and adult (4–6 months) mice were subjected to ex vivo global I/R. Augmented release of HSP27 in aging hearts was associated with greater production of cytokines (TNF-α and IL-1β) and worse functional recovery. Anti-HSP27 suppressed the inflammatory response and markedly improved functional recovery in aging hearts. Perfusion of recombinant HSP27 to aging hearts resulted in greater cytokine production and more severe contractile depression in comparison to adult hearts. TLR4 deficiency abolished cytokine production and functional injury in aging hearts exposed to recombinant HSP27. Interestingly, aging hearts had higher TLR4 protein levels and displayed enhanced TLR4-medi-ated NF-κB activation following HSP27 stimulation or I/R. Extracellular HSP27 and TLR4 jointly enhance the inflammatory response and hamper functional recovery following I/R in aging hearts. The enhanced inflammatory response to global I/R and attenuated postischemic functional recovery in aging hearts are due, at least in part, to augmented myocardial release of HSP27 and elevated myocardial TLR4 levels.