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 post-ischemic 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 is 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-mediated 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 post-ischemic functional recovery in aging hearts is due, at least in part, to augmented myocardial release of HSP27 and elevated myocardial TLR4 levels.
Highlights
Cardiac surgery is frequently performed in elderly patients for treatment of ischemic heart disease and calcific aortic valve disease
We examined the impact of aging on cardiac release of HSP27 during ischemia and reperfusion (I/R)
enzyme-linked immunosorbent assay (ELISA) assay revealed that cells from aging mice secrete a greater amount of HSP27 during hypoxia (Figure 1B)
Summary
Cardiac surgery is frequently performed in elderly patients for treatment of ischemic heart disease and calcific aortic valve disease. In animal models of global myocardial I/R, cardiac functional recovery is reduced in aging hearts [4,5,6]. While previous work on animal models suggests that a multifactorial mechanism may be involved in the exaggerated cardiac dysfunction in aging hearts [7,8], the mechanism responsible for the worsened outcome in the elderly after myocardial global I/R is incompletely understood [9]. Cardiac surgery with global myocardial I/R induces an inflammatory response in the myocardium characterized by the production and release of proinflammatory mediators [10,11,12,13,14,15]. Worsened myocardial injury after I/R in aging hearts is associated with enhanced myocardial production of proinflammatory mediators [19], the mechanism by which aging exaggerates the myocardial inflammatory response to I/R remains unclear
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