Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 306, Issue 6, Pages H882-H894Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00475.2013
Keywords
estrogen; mitochondrial damage; DAMPs; myocardial inflammation; heart failure; burn
Funding
- American Heart Association South Central Affiliate [09BGIA2220114]
- UTSW Department of Surgery
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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 17 beta-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). 17 beta-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-alpha, IL-1 beta, and IL-6), decrease in NF-kappa B 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 17 beta-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.
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