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Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced
Atsushi Tanaka1, Shinsuke Yuasa2, Giulia Mearini3
1Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (A.T., S.Y., T.E., T.S., M.K., D.K., Y.K., S.O., T.S., T.I., S.M., K.K., K.F.) Department of Cardiovascular Medicine, Saga University, Saga, Japan (A.T., K.N.).
Insights
Patient-specific stem cells reveal how genetic factors and endothelin-1 worsen hypertrophic cardiomyopathy (HCM) by inducing pathological phenotypes and contractile variability in heart cells.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Genetic Diseases
Background:
- Hypertrophic cardiomyopathy (HCM) pathogenesis remains unclear regarding genetic-environmental interactions.
- Patient-derived cardiomyocytes are difficult to obtain for research.
- Induced pluripotent stem cells (iPSCs) offer a promising model for studying HCM.
Purpose of the Study:
- To elucidate genetic-environmental interactions in HCM progression.
- To establish a human disease model for HCM using iPSCs.
- To identify environmental factors exacerbating HCM phenotypes.
Main Methods:
- Generated iPSCs from HCM patients and healthy controls.
- Differentiated iPSCs into cardiomyocytes for analysis.
- Stimulated cardiomyocytes with hypertrophy-promoting factors, including endothelin-1.
- Utilized high-speed video imaging for morphological and contractile analysis.
- Validated findings in mouse models.
Main Results:
- HCM iPSC-derived cardiomyocytes showed mild differences at baseline.
- Endothelin-1 significantly induced hypertrophy and myofibrillar disarray in HCM iPSC-cardiomyocytes.
- Contractile dynamics revealed variable directions in endothelin-1-stimulated HCM iPSC-cardiomyocytes.
- Phenotypes were replicated in Mybpc3-targeted mouse models.
Conclusions:
- Genetic background and endothelin-1 interact to promote HCM pathological phenotypes.
- Endothelin-1 exacerbates cardiomyocyte hypertrophy and disarray in an HCM iPSC model.
- HCM iPSC-derived cardiomyocytes exhibit contractile variability when exposed to endothelin-1.
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 cardiomyocytes 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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