• Jake J Wen, Keyan Mobli, Victoria G Rontoyanni, Claire B Cummins, Geetha L Radhakrishnan, Andrew Murton, and Ravi S Radhakrishnan.
• From the Departments of Surgery (Wen, Mobli, Rontoyanni, Cummins, Murton, RS Radhakrishnan), University of Texas Medical Branch at Galveston, Galveston, TX.
• J. Am. Coll. Surg. 2022 Apr 1; 234 (4): 660671660-671.

BackgroundOur previous studies have found that burn injury induces cardiac dysfunction through interruption of the antioxidant-response element (ARE) pathway in cardiac mitochondria. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator that activates many antioxidant enzymes. Oltipraz (Olti) is a Nrf2 activator and a well-known inducer of NQO1 along with other enzymes that comprise the Nrf2-associated antioxidants. We propose that Nrf2 activation will induce the ARE pathway, leading to abrogation of burn-induced cardiac dysfunction.Study DesignIn this study, we investigated the effect of Nrf2-deficiency in mice on burn-induced cardiac dysfunction. Wild-type (WT) and Nrf2-deficient mice received 30% total body surface area burn injury and were treated with or without Olti and then harvested at 3 hours and 24 hours post burn (3 hpb and 24 hpb).ResultsAs expected, Nrf2-deficient mice exhibited exacerbated cardiac dysfunction after burn injury, as measured by Vevo 2100 echocardiography. Electron microscopy showed that Nrf2 depletion worsened burn injury-induced cardiac mitochondrial damage. In addition, Nrf2 depletion increased cardiac mitochondrial dysfunction and myocardial fibrosis after burn injury. Treatment with Olti ameliorated the heart dysfunction in burned Nrf2-/+ mice, improved cardiac mitochondrial structure and oxidative phosphorylation, as well as decreased cardiac fibrosis. These results suggest that Nrf2 and its downstream targets modulate cardiac function after burn injury.ConclusionsIn summary, Nrf2 depletion worsens cardiac dysfunction after burn injury. Nrf2 activation, with a drug such as Olti, offers a promising therapeutic strategy for abrogating burn-induced cardiac dysfunction.Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.

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