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Epoxomicin Treatment before Ischemia Confers Cardioprotection through Up‐regulated Hsp22 Expression
Author(s) -
Li Dan,
Yoon Seong,
Park Misun,
Rashed Eman,
Dai Huacheng,
Park Jiyeon,
Sui Xiangzhen,
Vatner Dorothy,
Babu Gopal
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb622
Subject(s) - cardioprotection , pharmacology , downregulation and upregulation , reperfusion injury , hypoxia (environmental) , in vivo , ischemia , apoptosis , medicine , biology , chemistry , biochemistry , microbiology and biotechnology , organic chemistry , oxygen , gene
Background Cell death is the cause of infarct formation in ischemic myocardium. In this study, we demonstrate that Epoxomicin (Epox), a proteosome inhibitor formerly used as an anti‐cancer drug, confers effective cardioprotection. Methods and results The C57 mice (3.5 months, n=7) were injected i.p. with Epox (0.5 mg/kg/day) or vehicle for 2 weeks, and then subjected to 30 min ischemia followed by 24h reperfusion. Epox reduced the infarct size by 50% (p<0.05), despite of similar area‐at‐risk. To investigate the mechanism involved, in vitro study was performed on neonatal rat cardiac myocytes (NRCM). NRCM were treated with Epox (0.01μM) or veh for 24 hours, and then subjected to 36h hypoxia. Epox decreased hypoxia‐induced apoptosis by 50% (n=6; p<0.01). The protection was associated with up‐regulated expression of Hsp22 and its downstream effector iNOS. Deletion of Hsp22 in vitro and in vivo both abolished the iNOS expression and cardioprotection. Transcription activation analysis showed that HSF1 was highly activated in Epox treated NRCM. The Upregulation of Hsp22 expression was abolished upon the addition of KRIBB11, a specific inhibitor to HSF1. Conclusion Epox upregulates Hsp22 expression through HSF1 thereby provides cardioprotection, in vivo equivalent to preconditioning, against ischemia/reperfusion injury. Our data point to Epox as a promising therapeutic agent against ischemic heart disease.