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- W4313397117 abstract "Doxorubicin (Dox) is one of the most commonly used chemotherapy but also one of the most cardiotoxic. As of today, only the iron chelator Dexrazoxane has been FDA and EMA approved as a cardioprotective agent for Dox but its usage is still controversial. Thus, there is an urgent need to identify new targets to develop an effective protection against Dox-induced cardiotoxicity (DIC) without compromising its anti-tumor action. Well-characterized DIC mechanisms include topoisomerase II inhibition, DNA damages, induction of ROS and bioenergetic distress that lead to cardiomyocyte death. Alternative mechanisms are emerging such as an alteration of the β-adrenergic system. Our objective here was to study DIC mechanisms with a specific focus on how Dox treatment affects the β-adrenergic/cAMP signaling cascade. We used FRET-based sensors for cAMP targeted to two different cellular compartments, cytosol and nucleus, and measured the cAMP response to the β-adrenergic agonist isoprenaline (Iso, 10 nM) in adult rat ventricular myocytes after 24 h treatment with 1 or 10 μM Dox. Basal cAMP concentration was measured by Elisa. Adenylyl cyclase (AC5 and AC6 isoforms) mRNA was measured by RT-qPCR and phosphodiesterase (PDE) isoform expression and activity by western blot and radioenzymatic assay, respectively. cAMP response to Iso was decreased by 25% at 1 μM and > 50% at 10 μM Dox in both cytosol and nucleus. The maximal response to 20 μM L858051 (a forskolin analog) + 200 μM IBMX (a PDE inhibitor) on top of Iso was also decreased by Dox. Dox treatment did not change basal cAMP level nor PDE activity, but decreased AC5 and AC6 mRNA and PDE4 protein expression. Doxorubicin treatment downregulates the β-adrenergic/cAMP cascade in ventricular myocytes by decreasing adenylyl cyclase expression and maximal activity. This may contribute to the Dox-induced cardiotoxicity mechanisms." @default.
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- W4313397117 date "2022-12-01" @default.
- W4313397117 modified "2023-09-26" @default.
- W4313397117 title "β-adrenergic/cAMP signaling in doxorubicin-induced cardiotoxicity" @default.
- W4313397117 doi "https://doi.org/10.1016/j.yjmcc.2022.08.076" @default.
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