Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes

Atsushi Tanaka, Shinsuke Yuasa, Giulia Mearini, Toru Egashira, Tomohisa Seki, Masaki Kodaira, Dai Kusumoto, Yusuke Kuroda, Shinichiro Okata, Tomoyuki Suzuki, Taku Inohara, Takuro Arimura, Shinji Makino, Kensuke Kimura, Akinori Kimura, Tetsushi Furukawa, Lucie Carrier, Koichi Node, Keiichi Fukuda

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number001263
JournalJournal of the American Heart Association
Volume3
Issue number6
DOIs
Publication statusPublished - 2014

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Induced Pluripotent Stem Cells
Hypertrophic Cardiomyopathy
Endothelin-1
Cardiac Myocytes
Phenotype
Hypertrophy
Disease Progression
Molecular Biology
Healthy Volunteers

Keywords

  • Disease modeling
  • ET-1
  • HCM
  • IPS cells
  • MYBPC3

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes. / Tanaka, Atsushi; Yuasa, Shinsuke; Mearini, Giulia; Egashira, Toru; Seki, Tomohisa; Kodaira, Masaki; Kusumoto, Dai; Kuroda, Yusuke; Okata, Shinichiro; Suzuki, Tomoyuki; Inohara, Taku; Arimura, Takuro; Makino, Shinji; Kimura, Kensuke; Kimura, Akinori; Furukawa, Tetsushi; Carrier, Lucie; Node, Koichi; Fukuda, Keiichi.

In: Journal of the American Heart Association, Vol. 3, No. 6, 001263, 2014.

Research output: Contribution to journalArticle

Tanaka, A, Yuasa, S, Mearini, G, Egashira, T, Seki, T, Kodaira, M, Kusumoto, D, Kuroda, Y, Okata, S, Suzuki, T, Inohara, T, Arimura, T, Makino, S, Kimura, K, Kimura, A, Furukawa, T, Carrier, L, Node, K & Fukuda, K 2014, 'Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes', Journal of the American Heart Association, vol. 3, no. 6, 001263. https://doi.org/10.1161/JAHA.114.001263
Tanaka, Atsushi ; Yuasa, Shinsuke ; Mearini, Giulia ; Egashira, Toru ; Seki, Tomohisa ; Kodaira, Masaki ; Kusumoto, Dai ; Kuroda, Yusuke ; Okata, Shinichiro ; Suzuki, Tomoyuki ; Inohara, Taku ; Arimura, Takuro ; Makino, Shinji ; Kimura, Kensuke ; Kimura, Akinori ; Furukawa, Tetsushi ; Carrier, Lucie ; Node, Koichi ; Fukuda, Keiichi. / Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes. In: Journal of the American Heart Association. 2014 ; Vol. 3, No. 6.
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abstract = "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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AU - Tanaka, Atsushi

AU - Yuasa, Shinsuke

AU - Mearini, Giulia

AU - Egashira, Toru

AU - Seki, Tomohisa

AU - Kodaira, Masaki

AU - Kusumoto, Dai

AU - Kuroda, Yusuke

AU - Okata, Shinichiro

AU - Suzuki, Tomoyuki

AU - Inohara, Taku

AU - Arimura, Takuro

AU - Makino, Shinji

AU - Kimura, Kensuke

AU - Kimura, Akinori

AU - Furukawa, Tetsushi

AU - Carrier, Lucie

AU - Node, Koichi

AU - Fukuda, Keiichi

PY - 2014

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N2 - 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.

AB - 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.

KW - Disease modeling

KW - ET-1

KW - HCM

KW - IPS cells

KW - MYBPC3

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