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.