RT Journal Article SR Electronic T1 Coronary Microvascular Pericytes Are the Cellular Target of Sunitinib Malate–Induced Cardiotoxicity JF Science Translational Medicine FD American Association for the Advancement of Science SP 187ra69 OP 187ra69 DO 10.1126/scitranslmed.3005066 VO 5 IS 187 A1 Chintalgattu, Vishnu A1 Rees, Meredith L. A1 Culver, James C. A1 Goel, Aditya A1 Jiffar, Tilahu A1 Zhang, Jianhu A1 Dunner, Kenneth A1 Pati, Shibani A1 Bankson, James A. A1 Pasqualini, Renata A1 Arap, Wadih A1 Bryan, Nathan S. A1 Taegtmeyer, Heinrich A1 Langley, Robert R. A1 Yao, Hui A1 Kupferman, Michael E. A1 Entman, Mark L. A1 Dickinson, Mary E. A1 Khakoo, Aarif Y. YR 2013 UL http://stm.sciencemag.org/content/5/187/187ra69.abstract AB Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact platelet-derived growth factor receptor (PDGFR) signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anticancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.