Role of the adenosinergic system in anthracycline doxorubicin-induced cardiotoxicity

Abstract

The anthracycline doxorubicin (DOX) is a widely used anticancer drug, nonetheless, responsible for significant cardiotoxic effects. The mechanisms of this cardiotoxicity are not fully understood, although they seem to be mainly linked to mitochondrial dysfunctions, i.e. a decrease in ATP production and calcium overload. The ATP-derived adenosine and its A2A receptors (A2AR) have been shown to distinctly modulate in mice the DOX-induced cardiotoxicity, in a way dependent on the timing of A2AR activation during the cardiotoxic response (Hamad et al., 2009). On the other hand, in mouse chondrocytes, A2AR stimulation was able to improve mitochondrial metabolism (Castro et al., 2020). To better understand the impact of adenosine and its receptors in the DOX-induced cardiac toxicity, the development of human cellular models would be extremely important. Characterization of the role of A2AR in DOX-induced dysfunction in human endothelial cells and cardiomyocytes in order to better understand the pathophysiological mechanisms of this cellular cardiotoxicity. We used induced pluripotent stem cells (hiPSCs), differentiated into cardiomyocytes (CM) and endothelial cells (EC), treated with DOX (200 nM, 48 h), in the presence or absence of an A2AR agonist, CGS-21680 (70 nM, 24 h or 48 h). The differentiation of hiPSCs into CM and EC show all the expected characteristics of these cell types. We have verified the expression of A2AR, at the transcriptional and protein level, in both cell types and its quantification in the presence of DOX and/or CGS is in progress. Our preliminary results indicate a gene-expression regulation of A2AR-associated signaling pathways in these cellular models. The characterization of mitochondrial function in CM, and cytokine production in EC is currently under investigation. Our results will provide a better understanding of both the role of A2AR in DOX-induced cardiotoxicity and the implication of EC and CM in this cardiotoxicity. Moreover, this study will allow characterizing the A2AR intracellular signaling pathways functioning in hiPSCs-derived cardiac cells.