Prevention by dexrazoxane of down-regulation of ryanodine receptor gene expression in anthracycline cardiomyopathy in the rat

Anthracyclines can cause cumulative dose-related cardiotoxicity characteriz ed by changes in Ca2+ metabolism, including dysfunction of the sacroplasmic reticulum (SR) and decreased expression of Ca2+-handling proteins, such as the ryanodine receptor (RyR2). In this study, we examined the effect of de xrazoxane (ICRF-187), an iron chelator which prevents anthracycline cardiot oxicity, on RyR2 gene expression in rats treated chronically with daunorubi cin. Daunorubicin (2.5 mg kg(-1) i.v. weekly for 6 weeks) produced cardioto xicity as demonstrated by histopathologic changes. The ryanodine receptor/g lyceraldehyde phosphate dehydrogenase (GAPDH) mRNA ratio was decreased by 3 8+/-3% (P<0.02) compared to values in control rats. Dexrazoxane pre-treatme nt (50 mg kg(-1); 1 h prior to each daunorubicin injection) prevented the d ecrease in RyR2/GAPDH mRNA ratio and histopathologic lesions in daunorubici n-treated rats. This is the first report that a protective agent such as de xrazoxane can ameliorate the decreased expression of a specific gene involv ed in anthracycline-induced cardiotoxicity.