isolation-and-purification-of-murine-cardiac-pericytes

Isolation and Purification of Murine Cardiac Pericytes

Pericytes, perivascular cells of microvessels and capillaries, are known to play a part in angiogenesis, vessel stabilization, and endothelial barrier ...

Amgen Research and Discovery, Amgen Inc.

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.

Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity.

Le malate de sunitinib est un inhibiteur de kinase de tyrosine r&eacute;cepteur de multitargeted utilis&eacute; dans le traitement des cancers humains. Un grand nombre de patients trait&eacute;s par sunitinib d&eacute;velopper un dysfonctionnement cardiaque, mais le m&eacute;canisme de la cardiotoxicit&eacute; induite par le sunitinib est mal compris. Nous montrons que les souris trait&eacute;es avec le sunitinib d&eacute;veloppent un dysfonctionnement cardiaque et coronarien microvasculaire et pr&eacute;sentent une r&eacute;ponse cardiaque alt&eacute;r&eacute;e au stress. Les changements physiologiques provoqu&eacute;s par le traitement par sunitinib sont accompagn&eacute;s par un appauvrissement consid&eacute;rable des p&eacute;ricytes microvasculaire coronaire. P&eacute;ricytes sont un type de cellule qui est tributaire de la signalisation de r&eacute;cepteur (PDGFR) facteur de croissance d&eacute;riv&eacute; des plaquettes intact, mais dont le r&ocirc;le dans le coeur est mal d&eacute;fini. Appauvrissement de le pericyte induite par le sunitinib et dysfonction microvasculaire coronaire sont r&eacute;capitul&eacute;s par CP-673451, un inhibiteur PDGFR structurellement distinct, confirmant le r&ocirc;le de PDGFR survie pericyte. La thalidomide, un agent anticanc&eacute;reux qui est connu pour exercer des effets b&eacute;n&eacute;fiques sur la survie de le pericyte et la fonction, emp&ecirc;che la mort cellulaire induite par le sunitinib pericyte in vitro et cardiotoxicit&eacute; induite par le sunitinib in vivo dans un mod&egrave;le murin. Nos r&eacute;sultats sugg&egrave;rent que les p&eacute;ricytes sont la principale cible cellulaire de cardiotoxicit&eacute; induite par le sunitinib et r&eacute;v&egrave;lent le pericyte comme un type de cellules d&#39;int&eacute;r&ecirc;t dans la r&eacute;gulation de la fonction microvasculaire coronaire. En outre, nos donn&eacute;es fournissent des preuves pr&eacute;liminaires que la thalidomide peut emp&ecirc;cher la cardiotoxicit&eacute; chez les patients canc&eacute;reux trait&eacute;s sunitinib.

Vishnu Chintalgattu

Department of Cardiometabolic Disorders

Amgen Research and Discovery, Amgen Inc.

Isolation and Purification of Murine Cardiac Pericytes

Vishnu Chintalgattu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Cardiometabolic Disorders

Amgen Research and Discovery, Amgen Inc.

Isolation and Purification of Murine Cardiac Pericytes

Department of Cardiometabolic Disorders