Evaluation of the impact of the proteasome inhibitor on calcium channel expression in cardiomyocytes treated with doxorubicin
Curr Issues Pharm Med Sci., Vol. 31, No. 1, 18-21
Agnieszka Korga1, Milena Soroka1, Karolina Wicha1, Ewelina Humeniuk2,
Grzegorz Adamczuk2, Magdalena Iwan1, Marcin Sysa2, Jaroslaw Dudka2
One of the less known mechanisms of doxorubicin action is the effect on the functioning of the ubiquitin-proteasome degradation system (UPS). So far, the role of impaired proteasome activity in the development of anthracycline cardiomyopathy has not been clarified. It has been shown, however, that doxorubicin decreases the expression of proteins, including the expression of the calcium channel. However, it has not been established whether the observed disturbances are due to the activation of the UPS system by doxorubicin, or due to inhibition of translation or transcription. Therefore, the aim of the study was to evaluate the mRNA and protein expression of plasmalemmal (NaCaX, L-type) and sarcoplasmic reticulum (SERCA2, RyR2) channels in rat embryonic cardiomyocytes treated with doxorubicin and the proteasome inhibitor – bortezomib. The study was conducted utilizing the rat cardiomyocyte H9C2 line that was treated with doxorubicin and bortezomib in different concentrations. After 24 hours incubation, mRNA and protein expression analysis followed. The study did not show any universal mechanism of doxorubicin influence on calcium channel expression. With regard to the Na/Ca exchanger, we saw that DOX decreased the protein level in a proteasome activity-dependent manner. Moreover, we noted that the SERCA2 protein expression level was regulated by degradation intensity, however at the same time, no significant effect of doxorubicin on the level of this protein was demonstrated.
doxorubicin, bortezomib, proteasome, cardiotoxicity, calcium channels.