Everolimus Rescues the Phenotype of Elastin Insufficiency in Patient Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells
| العنوان: | Everolimus Rescues the Phenotype of Elastin Insufficiency in Patient Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells |
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| المؤلفون: | Milica Radisic, James Ellis, Deivid C. Rodrigues, Tadeo Thompson, Caroline Kinnear, Fred W. Keeley, Aric Pahnke, Samad Ahadian, Caitlin Loo, Rahul Agrawal, Oyediran Akinrinade, Seema Mital |
| المصدر: | Arteriosclerosis, Thrombosis, and Vascular Biology |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Williams Syndrome, Heterozygote, Vascular smooth muscle, Induced Pluripotent Stem Cells, Myocytes, Smooth Muscle, Cell, elastin, Arterial Occlusive Diseases, Constriction, Pathologic, Biology, medicine.disease_cause, Muscle, Smooth, Vascular, Cell Line, Translational Sciences, stem cells, medicine, Humans, Everolimus, genes, Induced pluripotent stem cell, Protein Kinase Inhibitors, Cell Proliferation, Mutation, TOR Serine-Threonine Kinases, Infant, Cell Differentiation, Phenotype, medicine.anatomical_structure, Case-Control Studies, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, cardiovascular system, Cancer research, biology.protein, vascular diseases, Female, Stem cell, Cardiology and Cardiovascular Medicine, Elastin, medicine.drug |
| الوصف: | Supplemental Digital Content is available in the text. Objective: Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells–derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except one Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy. Conclusions: Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy. |
| تدمد: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.119.313936 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::019bc59c2fdd693bb3ce333b4f190a21 https://doi.org/10.1161/atvbaha.119.313936 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....019bc59c2fdd693bb3ce333b4f190a21 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244636 10795642 |
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| DOI: | 10.1161/atvbaha.119.313936 |