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- W2034931179 abstract "Doxorubicin is a powerful chemotherapeutic agent used to treat breast cancer. Doxorubicin's use is limited due to the development of cardiotoxic side effects including arrhythmia and heart failure. Acute doxorubicin cardiotoxicity is multifaceted and includes the formation of reactive oxygen species, apoptosis, and disturbances in calcium handling within the intracellular sarcoplasmic reticulum (SR) store. Our focus is on the protein targets within the SR that bind doxorubicin, namely the ryanodine receptor (RyR2) calcium release channel and the calcium binding protein, calsequestrin (CSQ2) which also regulates RyR2, and how drug binding disturbs SR calcium homeostasis. Such disturbances are known to cause cardiac dysfunction. Our previous in vitro assays showed that doxorubicin reduced CSQ2's calcium binding capacity, altered SR calcium homeostasis and impaired RyR2 activity, as a consequence of the drug binding directly to these proteins and to drug-induced RyR2 oxidation. To investigate the in vivo modifications of RyR2 and other SR proteins by doxorubicin, we developed an acute mouse model of doxorubicin cardiotoxicity. Doxorubicin treatment reduced expression of RyR2, the SR calcium pump SERCA and CSQ2 and lowered the fraction of CSQ2 associated with RyR2. The decline in SERCA and RyR2 expression and the reduced proportion of RyR2 that can be activated by CSQ2 may underlie the significantly perturbed SR calcium release after doxorubicin treatment. In addition, doxorubicin treatment caused “hyper” phosphorylation of RyR2 at S2808 and significant dissociation of the RyR2 dephosphorylating enzymes PP1 and PP2A. Hyperphosphorylation of S2808 is known to cause RyR2 dysfunction, after-depolarizations, arrhythmia and heart failure. It is likely other modifications in RyR2 function (oxidation, ligand-binding) in addition to RyR2 hyperphosphorylation and reduced CSQ association underlie the multi-faceted disturbances in calcium release that contribute to the clinical cardiotoxicity induced by doxorubicin treatment." @default.
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- W2034931179 date "2012-01-01" @default.
- W2034931179 modified "2023-10-18" @default.
- W2034931179 title "Acute Chemotherapeutic Treatment Induces Chronic Phosphorylation of the Cardiac Ryanodine Receptor" @default.
- W2034931179 doi "https://doi.org/10.1016/j.bpj.2011.11.3018" @default.
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