title: Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity.
abstract: 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.
authors.affiliation: Metabolic Disorders, Amgen Inc., Research, South San Francisco, CA, USA. vishnuc@amgen.com
authors.forename: Vishnu
authors.initials: V
authors.lastname: Chintalgattu
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Rees
authors.forename: James C
authors.initials: JC
authors.lastname: Culver
authors.forename: Aditya
authors.initials: A
authors.lastname: Goel
authors.forename: Tilahu
authors.initials: T
authors.lastname: Jiffar
authors.forename: Jianhu
authors.initials: J
authors.lastname: Zhang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dunner
authors.forename: Shibani
authors.initials: S
authors.lastname: Pati
authors.forename: James A
authors.initials: JA
authors.lastname: Bankson
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kupferman
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Mary E
authors.initials: ME
authors.lastname: Dickinson
authors.forename: Aarif Y
authors.initials: AY
authors.lastname: Khakoo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology / Q000187:drug effects*; D020286:Pericytes / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib