A contraction stress model of hypertrophic cardiomyopathy due to thick filament sarcomere mutations
| Autor: | Feria A. Ladha, Andre Lowe, Yu-Sheng Chen, Bryan D. Huey, Rachel Cohn, Anthony M. Pettinato, Ketan Thakar, Hinson Jt, Emily Meredith, Katherine Atamanuk |
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| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
Contraction (grammar) Hypertrophic cardiomyopathy macromolecular substances 030204 cardiovascular system & hematology Biology medicine.disease medicine.disease_cause Sarcomere 3. Good health Sudden cardiac death Cell biology 03 medical and health sciences 0302 clinical medicine Heart failure Myosin cardiovascular system medicine cardiovascular diseases Induced pluripotent stem cell Oxidative stress 030304 developmental biology |
| Popis: | Thick filament sarcomere mutations are the most common cause of hypertrophic cardiomyopathy (HCM), a disorder of heart muscle thickening associated with sudden cardiac death and heart failure, with unclear mechanisms. We engineered an isogenic panel of four human HCM induced pluripotent stem cell (iPSc) models using CRISPR/Cas9, and studied iPSc-derived cardiomyocytes (iCMs) in 3-dimensional cardiac microtissue (CMT) assays that resemble in vivo cardiac architecture and biomechanics. HCM mutations result in hypercontractility in association with prolonged relaxation kinetics in proportion to mutation pathogenicity but not calcium dysregulation. RNA sequencing and protein expression studies identified that HCM mutations result in p53 activation secondary to increased oxidative stress, which results in increased cytotoxicity that can be reversed by p53 genetic ablation. Our findings implicate hypercontractility as an early consequence of thick filament mutations, and the p53 pathway as a molecular marker and candidate therapeutic target for thick filament HCM. |
| Databáze: | OpenAIRE |
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