Edaravone Improves Septic Cardiac Function by Inducing an HIF‐1α/HO‐1 Pathway

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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.
Funding Information
  • Natural Science Foundation of Hunan Province (2017JJ3438, 2017JJ3448)
  • National Natural Science Foundation of China (81600251)

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