Increased Afterload Augments Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model
| Autor: | Rachel Truitt, Alexia Vite, Kenneth B. Margulies, Anbin Mu, Elise A. Corbin, Jeffrey Brandimarto, Bonnie Ky |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Force generation lcsh:Diseases of the circulatory (Cardiovascular) system sunitinib 030204 cardiovascular system & hematology Pharmacology DMSO dimethyl sulfoxide urologic and male genital diseases Tyrosine-kinase inhibitor PRECLINICAL RESEARCH 0302 clinical medicine tyrosine kinase inhibitors Medicine huMSC human mesenchymal stem cell RPMI Roswell Park Memorial Institute medium Membrane potential AMPK adenosine monophosphate-activated protein kinase Sunitinib apoptosis female genital diseases and pregnancy complications 3. Good health tissue engineering cardiovascular system PDMS polydimethylsiloxane Cardiology and Cardiovascular Medicine medicine.drug toxicology congenital hereditary and neonatal diseases and abnormalities ATP adenosine triphosphate medicine.drug_class NRVM neonatal rat ventricular myocyte cardiotoxicity EDTA ethylenediamine tetraacetic acid 03 medical and health sciences Afterload iPS-CM induced pluripotent stem cell-derived cardiomyocyte 3D 3-dimensional CCCP carbonyl cyanide m-chlorophenyl hydrazine In patient TMRM tetramethylrhodamine CMT cardiac microtissue Cardiotoxicity business.industry afterload nervous system diseases 030104 developmental biology LV left ventricle Apoptosis AICAR 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside lcsh:RC666-701 2D 2-dimensional Hu-iPS-CM human induced pluripotent stem cell cardiomyocyte business |
| Zdroj: | JACC: Basic to Translational Science, Vol 3, Iss 2, Pp 265-276 (2018) JACC: Basic to Translational Science |
| Popis: | Visual Abstract Highlights • Sunitinib, an oral tyrosine kinase inhibitor used widely to treat solid organ tumors, frequently induces hypertension and causes LV dysfunction in up to 19% of treated individuals. • Sunitinib-induced cardiotoxicity can be modeled using engineered CMT. • In CMT, sunitinib induces dose- and duration-dependent activation of apoptosis pathways and decreases in CMT force generation, spontaneous beating, and mitochondrial membrane potential. • Exposure of CMT to increased in vitro afterload intensifies the cardiotoxicity of clinically relevant sunitinib concentrations. • These findings suggest that intensive antihypertensive therapy may be an appropriate strategy to mitigate LV dysfunction observed in patients treated with sunitinib. Summary Sunitinib, a multitargeted oral tyrosine kinase inhibitor, used widely to treat solid tumors, results in hypertension in up to 47% and left ventricular dysfunction in up to 19% of treated individuals. The relative contribution of afterload toward inducing cardiac dysfunction with sunitinib treatment remains unknown. We created a preclinical model of sunitinib cardiotoxicity using engineered microtissues that exhibited cardiomyocyte death, decreases in force generation, and spontaneous beating at clinically relevant doses. Simulated increases in afterload augmented sunitinib cardiotoxicity in both rat and human microtissues, which suggest that antihypertensive therapy may be a strategy to prevent left ventricular dysfunction in patients treated with sunitinib. |
| Databáze: | OpenAIRE |
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