Abstract
High-mobility group box-1 (HMGB1) acts as a proinflammatory cytokine that triggers and amplifies the inflammation cascade following ischemia/reperfusion (I/R). Ethyl pyruvate (EP) has been reported to inhibit HMGB1 release in several I/R models. This study was designed to investigate the potential role of HMGB1 in a rat myocardial I/R model and to determine the effect of EP. Male Sprague Dawley rats were subjected to 30 min myocardial ischemia and 48 h reperfusion. In protocol 1, the rats were assigned to one of four groups (n=16 per group): Phosphate-buffered saline (PBS) or recombinant human HMGB1 (rhHMGB1) at three different doses (1, 10 or 100 μg/kg). In protocol 2, the rats were also assigned to one of four groups (n=16 per group): Sham, control, EP and EP + rhHMGB1. EP (40 mg/kg) or rhHMGB1 (100 μg/kg) was injected intravenously prior to reperfusion. Hemodynamic measurements were performed, and myocardial infarct size (IS) was calculated. Western blotting was conducted to evaluate HMGB1, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) expression levels. In the protocol 1 rats, the IS was markedly increased in the rhHMGB1 (100 μg/kg) group compared with that in the PBS group, and this increase was accompanied by elevated levels of TNF-α and IL-6. In the protocol 2 rats, I/R resulted a 4.8-fold increase in HMGB1 expression with an increased IS and impaired cardiac function compared with the sham group. EP significantly inhibited the elevated HMGB1 level, suppressed the activated TNF-α and IL-6 and reduced cardiac dysfunction. This cardioprotection was abolished by rhHMGB1. In conclusion, accumulation of HMGB1 is deleterious to the heart following myocardial I/R. EP can exert a strong protective effect against myocardial I/R injury, and these benefits are associated with a reduction in HMGB1.
Highlights
For patients with acute myocardial infarction, early reperfusion of the ischemic myocardium, either through thrombolytic therapy or primary percutaneous coronary intervention, is the most effective treatment to limit the infarct size (IS) and improve the clinical outcome; the process of restoring blood flow to the ischemic myocardium has the potential to induce additional lethal injuries and reduce myocardial salvage
In protocol 1, no significant difference in IS was detected among the Phosphate‐buffered saline (PBS), 1 and 10 μg/kg recombinant human HMGB1 (rhHMGB1) groups (IS/area at risk (AAR) 41.6±3.3, 42.3±3.1 and 43.7±3.2% respectively; P>0.05, Fig. 1)
Compared with the PBS group, administration of rhHMGB1 at a dose of 100 μg/kg resulted in a significant increase in IS/AAR (56.4±6.9% vs. PBS group, P
Summary
For patients with acute myocardial infarction, early reperfusion of the ischemic myocardium, either through thrombolytic therapy or primary percutaneous coronary intervention, is the most effective treatment to limit the infarct size (IS) and improve the clinical outcome; the process of restoring blood flow to the ischemic myocardium has the potential to induce additional lethal injuries and reduce myocardial salvage. Inflammatory cells and cytokines play an important role in the pathogenesis of myocardial reperfusion injury, by triggering deleterious responses and by amplifying ongoing responses to build a cascade of injury [1]. Numerous experimental studies have demonstrated the efficacy of anti‐inflammation therapies against myocardial ischemia/reperfusion (I/R); the translation of these beneficial effects into the clinical setting has been disappointing [1,2]. Recent studies have shown that HMGB1, acting via the receptor for advanced glycation end products (RAGE) or members of the Toll‐like family of receptors (TLRs), is an early mediator of organ damage in myocardial I/R injury [4,5]. The aims of the present study were to investigate the role of HMGB1 in a myocardial I/R model, to explore the association between HMGB1 and the inflammatory mediators and to determine the benefit of EP
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