Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs.
Mitochondria-derived danger-associated molecular patterns (DAMPs) play important roles in sterile inflammation after acute injuries. This study was designed to test the hypothesis that 17β-estradiol protects the heart via suppressing myocardial mitochondrial DAMPs after burn injury using an animal model. Sprague-Dawley rats were given a third-degree scald burn comprising 40% total body surface area (TBSA). 17β-Estradiol, 0.5 mg/kg, or control vehicle was administered subcutaneously 15 min following burn. The heart was harvested 24 h postburn. Estradiol showed significant inhibition on the productivity of H2O2 and oxidation of lipid molecules in the mitochondria. Estradiol increased mitochondrial antioxidant defense via enhancing the activities and expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Estradiol also protected mitochondrial respiratory function and structural integrity. In parallel, estradiol remarkably decreased burn-induced release of mitochondrial cytochrome c and mitochondrial DNA (mtDNA) into cytoplasm. Further, estradiol inhibited myocardial apoptosis, shown by its suppression on DNA laddering and downregulation of caspase 1 and caspase 3. Estradiol's anti-inflammatory effect was demonstrated by reduction in systemic and cardiac cytokines (TNF-α, IL-1β, and IL-6), decrease in NF-κB activation, and attenuation of the expression of inflammasome component ASC in the heart of burned rats. Estradiol-provided cardiac protection was shown by reduction in myocardial injury marker troponin-I, amendment of heart morphology, and improvement of cardiac contractility after burn injury. Together, these data suggest that postburn administration of 17β-estradiol protects the heart via an effective control over the generation of mitochondrial DAMPs (mtROS, cytochrome c, and mtDNA) that incite cardiac apoptosis and inflammation.
Departments of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
Xiao
X
Yao
Jane G
JG
Wigginton
David L
DL
Maass
Lisha
L
Ma
Deborah
D
Carlson
Steven E
SE
Wolf
Joseph P
JP
Minei
Qun S
QS
Zang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002056:Burns / Q000150:complications / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
D002316:Cardiotonic Agents; D016207:Cytokines; D004272:DNA, Mitochondrial; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D004958:Estradiol; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D020169:Caspases
DAMPs; burn; estrogen; heart failure; mitochondrial damage; myocardial inflammation