Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 3, Issue 6, Pages -Publisher
WILEY-BLACKWELL
DOI: 10.1161/JAHA.114.001263
Keywords
disease modeling; ET-1; HCM; iPS cells; MYBPC3
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Health Labour Sciences Research Grant
- New Energy and Industrial Technology Development Organization, Japan
- Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation
- Japan Science and Technology Agency
- Research Center Network for Realization of Regenerative Medicine The Program for Intractable Diseases Research utilizing Disease-specific iPS cells
- Nakatomi Foundation
- Japan Heart Foundation/Novartis Grant for Research Award on Molecular and Cellular Cardiology SENSHIN Medical Research Foundation
- Kimura Memorial Heart Foundation Research Grant
- Japan Intractable Diseases Research Foundation, Japan
- Cell Science Research Foundation
- Tokyo Biochemical Research Foundation
- Suzuken Memorial Foundation
- Japan Foundation for Applied Enzymology
- Joint Usage/Research Program of Medical Research Institute
- Tokyo Medical and Dental University
- DZHK (German Center for Cardiovascular Research)
- German Ministry of Research and Education (BMBF)
- Association Institut de Myologie (Paris)
- Grants-in-Aid for Scientific Research [25670126, 25293181] Funding Source: KAKEN
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Background-Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM. Methods and Results-We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardi omyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions. Conclusions-Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.
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