Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against Doxorubicin-induced cardiotoxicity

Abstract Aims Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. Method and Results Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38 CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in WT but not in CD38CI mice treated with DXR. Second, blocking CD38 NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. Reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. Conclusions NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model. Translational perspective Specific and non-cytotoxic ecto-NADase anti-CD38 antibodies may be a potential therapy for anthracyclines-induced cardiac dysfunction.