A modification of cAMP compartmentation is involved in the doxorubicin-induced cardiotoxicity

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-known and studied DIC mechanisms include Topoisomerase II inhibition, DNA damages, induction of ROS and bioenergetic distress that lead to the death of the cardiomyocyte. Alternative mechanisms are emerging such as the alteration of the ß adrenergic system. cAMP is one of the most important second messengers in the heart and is found compartmentalized in specific subcellular domain modulating downstream effectors and thus many physiological processes (contraction/relaxation). Our objective is to study DIC mechanisms with a specific focus on Dox effect on the ß adrenergic system and especially on the cAMP compartmentation. We used FRET-based sensors for cAMP targeted to different compartment of the cell (cytosol and nucleus) in order to study cAMP production in adult rat ventricular myocyte under Isoprenalin stimulation after Dox treatment. Involvement of the main molecular actors of the cAMP compartmentation system has been studied. Under β adrenergic stimulation, cAMP production decreases in the Dox treated cells compare to the control, in the cytosol as well as in the nucleus. Furthermore, the maximal level of cAMP production reached by the Dox treated myocytes is also lower than the control. Based on this data we looked at the expression of AC5 and 6, the two most expressed in myocytes. AC5 but not AC6 mRNA expression is decreased by Dox treatment indicating a potential implication of AC5 in the DIC. Moreover, PDEs involvement cannot be exclude yet. Here, we show for the first time the involvement of cAMP compartmentation in the DIC.