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Prevention by dexrazoxane of down‐regulation of ryanodine receptor gene expression in anthracycline cardiomyopathy in the rat
Author(s) -
Burke Briant E,
Gambliel Hervé,
Olson Richard D,
Bauer Frederic K,
Cusack Barry J
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703538
Subject(s) - dexrazoxane , ryanodine receptor , anthracycline , cardiomyopathy , gene expression , biology , medicine , gene , receptor , endocrinology , pharmacology , genetics , heart failure , cancer , breast cancer
Anthracyclines can cause cumulative dose‐related cardiotoxicity characterized by changes in Ca 2+ metabolism, including dysfunction of the sacroplasmic reticulum (SR) and decreased expression of Ca 2+ ‐handling proteins, such as the ryanodine receptor (RyR2). In this study, we examined the effect of dexrazoxane (ICRF‐187), an iron chelator which prevents anthracycline cardiotoxicity, on RyR2 gene expression in rats treated chronically with daunorubicin. Daunorubicin (2.5 mg kg −1 i.v. weekly for 6 weeks) produced cardiotoxicity as demonstrated by histopathologic changes. The ryanodine receptor/glyceraldehyde phosphate dehydrogenase (GAPDH) mRNA ratio was decreased by 38±3% ( P <0.02) compared to values in control rats. Dexrazoxane pre‐treatment (50 mg kg −1 ; 1 h prior to each daunorubicin injection) prevented the decrease in RyR2/GAPDH mRNA ratio and histopathologic lesions in daunorubicin‐treated rats. This is the first report that a protective agent such as dexrazoxane can ameliorate the decreased expression of a specific gene involved in anthracycline‐induced cardiotoxicity. British Journal of Pharmacology (2000) 131 , 1–4; doi: 10.1038/sj.bjp.0703538