Cardiac Metabolic Deregulation Induced by the Tyrosine Kinase Receptor Inhibitor Sunitinib is rescued by Endothelin Receptor Antagonism.
The growing field of cardio-oncology addresses the side effects of cancer treatment on the cardiovascular system. Here, we explored the cardiotoxicity of the antiangiogenic therapy, sunitinib, in the mouse heart from a diagnostic and therapeutic perspective. We showed that sunitinib induces an anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis and reduced left ventricular ejection fraction as demonstrated by echocardiography. The capacity of positron emission tomography with [18F]fluorodeoxyglucose to detect the changes in cardiac metabolism caused by sunitinib was dependent on fasting status and duration of treatment. Pan proteomic analysis in the myocardium showed that sunitinib induced (i) an early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and (ii) a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes. Co-administration of the endothelin receptor antagonist, macitentan, to sunitinib-treated animals prevented both metabolic defects, restored glucose uptake and cardiac function, and prevented myocardial fibrosis. These results support the endothelin system in mediating the cardiotoxic effects of sunitinib and endothelin receptor antagonism as a potential therapeutic approach to prevent cardiotoxicity. Furthermore, metabolic and functional imaging can monitor the cardiotoxic effects and the benefits of endothelin antagonism in a theranostic approach.
['Sourdon|Joevin|J|', 'Lager|Franck|F|', 'Viel|Thomas|T|', 'Balvay|Daniel|D|', 'Moorhouse|Rebecca|R|', 'Bennana|Evangeline|E|', 'Renault|Gilles|G|', 'Tharaux|Pierre-Louis|PL|', 'Dhaun|Neeraj|N|', 'Tavitian|Bertrand|B|']
D000693:Anaerobiosis D000818:Animals D000970:Antineoplastic Agents D065128:Endothelin Receptor Antagonists D006019:Glycolysis D007211:Indoles D008810:Mice, Inbred C57BL D009206:Myocardium D020543:Proteome D011758:Pyrroles D020794:Receptor Protein-Tyrosine Kinases D000077210:Sunitinib
sunitinib endothelin cardio-oncology cardiotoxicity echocardiography positron emission tomography macitentan.