TY - JOUR
T1 - Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity
AU - Chintalgattu, Vishnu
AU - Rees, Meredith L.
AU - Culver, James C.
AU - Goel, Aditya
AU - Jiffar, Tilahu
AU - Zhang, Jianhu
AU - Dunner, Kenneth
AU - Pati, Shibani
AU - Bankson, James A.
AU - Pasqualini, Renata
AU - Arap, Wadih
AU - Bryan, Nathan S.
AU - Taegtmeyer, Heinrich
AU - Langley, Robert R.
AU - Yao, Hui
AU - Kupferman, Michael E.
AU - Entman, Mark L.
AU - Dickinson, Mary E.
AU - Khakoo, Aarif Y.
PY - 2013/5/29
Y1 - 2013/5/29
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84880566944&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880566944&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3005066
DO - 10.1126/scitranslmed.3005066
M3 - Article
C2 - 23720580
AN - SCOPUS:84880566944
SN - 1946-6234
VL - 5
JO - Science translational medicine
JF - Science translational medicine
IS - 187
M1 - 187ra69
ER -