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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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Chintalgattu V,Rees ML,Culver JC,Goel A,Jiffar T,Zhang J,Dunner K Jr,Pati S,Bankson JA,Pasqualini R,Arap W,Bryan NS,Taegtmeyer H,Langley RR,Yao H,Kupferman ME,Entman ML,Dickinson ME,Khakoo AY

doi

10.1126/scitranslmed.3005066

subject

Has Abstract

pub_date

2013-05-29 00:00:00

pages

187ra69

issue

187

eissn

1946-6234

issn

1946-6242

pii

5/187/187ra69

journal_volume

5

pub_type

杂志文章

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