Disruption of endothelial cell intraflagellar transport protein 88 exacerbates doxorubicin-induced cardiotoxicity

Abstract Aims Doxorubicin (DOX) is a potent anticancer drug with severe dose-dependent cardiotoxicity. To address this issue, previous research has primarily focused on DOX-induced toxicity on cardiomyocyte. However, research has refocused on the endothelium as a therapeutic target due to the emerging role of endothelial cells in support of cardiomyocyte survival and function. Main methods We investigated a novel role of endothelial cell primary cilia in the prevention of DOX-mediated cardiotoxicity. Mice lacking endothelial cell primary cilia, via the deletion of endothelial cell-specific intraflagellar protein 88 (IFT88) expression, were administered DOX (20 mg/kg i.p.), and assessed for survival, cardiac function, cardiac structure changes, and indices of cardiomyocyte injury. Key findings Compared to wild-type littermates, DOX-treatment resulted in reduced survival and measurements of cardiac function (ejection fraction and fractional shortening) in EC-IFT88−/− mice. Cardiomyocyte vacuolization, cardiac fibrosis, and serum CK-MB levels were increased in DOX-treated animals compared to SAL-treated controls. However, these parameters were not significantly different when comparing WT and EC-IFT88−/− mice after DOX treatment. Significance The loss of endothelial cell primary cilia accelerated DOX-mediated mortality and reduced cardiac function, suggesting pathways downstream of ciliary-mediated signal transduction as potential targets to promote EC support of cardiomyocyte function during DOX treatment.