Abstract
Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.
Highlights
Sepsis, a systemic deleterious inflammatory response to infection or injury [1], has long been associated with high mortality rate, which mainly results from multiorgan dysfunction and failure [2]
As demonstrated in the H&E staining of the myocardium (Figure 1(a)), the normal architecture of the myocardium as shown in the sham group was deformed after cecal ligation and puncture (CLP)
We have shown that EDA can alleviate septic myocardial dysfunction by reducing cardiac oxidative stress through the hypoxia-inducible factor- (HIF-)1α/heme oxygenase- (HO-)1 pathway
Summary
A systemic deleterious inflammatory response to infection or injury [1], has long been associated with high mortality rate, which mainly results from multiorgan dysfunction and failure [2]. Cardiac dysfunction is highly prevalent during sepsis, which is a major cause of high mortality rate in septic patients [3,4,5,6]. Therapy for this lethal disease is nonspecific and often not effective as current understanding of its pathophysiology remains elusive [7]. While the antioxidative effect of EDA has been documented in brain [15], pulmonary [16], liver [17], and renal injuries [18], less is known of its effect in septic cardiac complications
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