Cardiac Dysfunction after Burn Injury: Role of the AMPK-SIRT1-PGC1α-NFE2L2-ARE Pathway

BACKGROUND: Mitochondrial oxidative stress plays a prominent role in the development of burn-induced cardiac dysfunction. AMP-activated kinase (AMPK), an energy sensor, has a central role in the pathogenesis of heart failure. However, its role in cardiac dysfunction after burn injury is unclear. Our hypothesis is that burn injury acts through the AMPK-sirtuin 1-PGC1 alpha-nuclear factor erythroid 2-related factor 2 (NFE2L2)-ARE signaling pathway, leading to cardiac mitochondrial impairment, resulting in cardiac dysfunction. STUDY DESIGN: Male Sprague-Dawley rats underwent sham procedure or 60% total body surface area full-thickness burn. Echocardiograms were performed 24 hours post burn. Heart tissue was harvested at 24 hours post burn for biochemistry/molecular biologic analysis. AC16 cardiomyocytes were treated with either sham or burned rat serum (+/- AMPK inhibitor/AMPK activator/PGC1 alpha activator) for evaluation of cardiomyocyte mitochondrial function by using seahorse in vitro. RESULTS: Burn injury-induced cardiac dysfunction was measured by echocardiogram. Burn injury suppressed cardiac AMPK, sirtuin 1, and PGC1 expression, leading to acetylation of cardiomyocyte proteins. In addition, burn injury caused NFE2L2 and NFE2L2 regulated antioxidants (heme oxygenase 1, NADH quinone oxidoreductase 1, glutamatecysteine ligase catalytic subunit, manganese superoxide dismutase, and glutathione peroxidase) to decrease, resulting in cardiac oxidative stress. In vitro, AMPK1 activator and PGC1 alpha agonist treatment improved Ac16 cell mitochondrial dysfunction, and AMPK1 inhibitor treatment worsened Ac16 cellular damage. CONCLUSIONS: Burn-induced cardiac dysfunction and cardiac mitochondrial damage occur via the AMPK-sirtuin 1-PGC1 alpha-NFE2L2-ARE signaling pathway. AMPK and PGC1 alpha agonists might be promising therapeutic agents to reverse cardiac dysfunction after burn injury. ((C) 2020 Published by Elsevier Inc. on behalf of the American College of Surgeons.)