Tamoxifen protects against acute tumor necrosis factor alpha-induced cardiac injury via improving mitochondrial functions.
Tamoxifen is the most commonly used antiestrogen for the treatment of breast cancer. Several clinical trials demonstrate that tamoxifen reduces the risk of heart disease and osteoporosis. However, the mechanism by which tamoxifen causes cardioprotection is unclear. Because increased levels of tumor necrosis factor alpha (TNFalpha) in tissue and/or plasma have been observed in virtually all forms of cardiac injury, we investigated whether tamoxifen prevents cardiac injury in a murine model of acute TNFalpha challenge. Five- to six-week-old female mice were injected (ip) with tamoxifen at 0.25 mg/kg daily for 3 or 7 days before receiving an injection of TNFalpha. Ultrastructural examination of cardiac tissues revealed remarkable protection against TNFalpha-induced mitochondrial damage in tamoxifen pretreated mice. Tamoxifen treatment significantly improved the mitochondrial respiratory function and enhanced superoxide-scavenging activity of mitochondria. These findings reveal a novel mitochondria-mediated mechanism by which tamoxifen exerts its cardiac protection effect against acute TNFalpha-induced heart injury.
Zhao
Yunfeng
Y
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Wang
Li-ming
LM
Chaiswing
Luksana
L
Yen
Hsiu-chuan
HC
Oberley
Terry D
TD
Lien
Yu-chin
YC
Lin
Shu-mei
SM
Mattson
Mark P
MP
St Clair
Daret
D
D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D042967:Electron Transport Complex I / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D002316:Cardiotonic Agents; D016166:Free Radical Scavengers; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; D013481:Superoxides; C069521:recombinant human tumor necrosis factor-binding protein-1; D042967:Electron Transport Complex I