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"Long-term Epoxomicin Treatment Protects the Heart against Ischemia/Reperfusion Injury"

by
Dan Li
Cell Biology and Molecular Medicine Program
B.S. 2004, Yunnan University, China


Thesis Advisor: Gopal J. Babu, Ph.D.
Assistant Professor
Department of Cell Biology and Molecular Medicine

Wednesday, January 8, 2014
10:00 A.M., MSB-G609


Abstract

Cell death (both apoptosis and necrosis) is the most important cause of the infarct formation after ischemia/reperfusion injury, which eventually leads to heart failure. However, there is no effective therapy so far that reduces cell death. In this study, we demonstrate that epoxomicin, a proteasome inhibitor formerly used as an anti-cancer drug, confers effective cardioprotection against Ischemia/Reperfusion injury. The C57 mice were intraperitoneally injected daily with epoxomicin (0.5 mg/kg/day) or vehicle for 2 weeks, and then subjected to 30 min ischemia followed by 24h reperfusion. Results show that epoxomicin treatment reduced the infarct size by 50% (p<0.05), despite of similar area-at-risk. To investigate the mechanism(s) involved in epoxomicin mediated cardioprotection, in vitro study was performed on neonatal rat cardiac myocytes (NRCM). NRCM were treated with epoxomicin (10nM) or vehicle for 24 hours, and then subjected to 36 hours of hypoxia. Epoxomicin treatment decreased the hypoxia-induced apoptosis by 50% (n=6; p<0.01) as measured by TUNEL, compared to the vehicle-treated controls. Western blot analysis showed upregulation of H11k and its downstream effector iNOS in epoxomicin treated NRCM. Ablation of H11k expression abolished the epoxomicin induced iNOS expression as well as the cardioprotection. Transcription activation analysis identified the activation of heat shock factor-1 (HSF1) in epoxomicin treated NRCM. In agreement with the gene expression analysis, silencing of HSF1 expression abolished the epoxomicin mediated H11k upregulation and cytoprotection. These data indicate that epoxomicin protects the myocardium against ischemia/reperfusion injury via the activation of H11k-iNOS signaling pathway. In conclusion, our studies suggest that epoxomicin treatment is equivalent to preconditioning and could be used as a therapeutic agent in protecting the myocardium against ischemic heart disease.


Keywords: Epoxomicin, Myocardium, Ischemia, Infarction, Preconditioning, H11k, HSF1, iNOS


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