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


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.
Department 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.).
Atsushi
A
Tanaka
Department 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.).
Shinsuke
S
Yuasa
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (G.M., L.C.) DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany (G.M., L.C.).
Giulia
G
Mearini
Department 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.).
Toru
T
Egashira
Department 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.).
Tomohisa
T
Seki
Department 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.).
Masaki
M
Kodaira
Department 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.).
Dai
D
Kusumoto
Department 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.).
Yusuke
Y
Kuroda
Department 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 Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (S.O., T.F.).
Shinichiro
S
Okata
Department 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.).
Tomoyuki
T
Suzuki
Department 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.).
Taku
T
Inohara
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.A., A.K.).
Takuro
T
Arimura
Department 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.).
Shinji
S
Makino
Department 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.).
Kensuke
K
Kimura
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.A., A.K.).
Akinori
A
Kimura
Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (S.O., T.F.).
Tetsushi
T
Furukawa
Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (G.M., L.C.) DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany (G.M., L.C.).
Lucie
L
Carrier
Department of Cardiovascular Medicine, Saga University, Saga, Japan (A.T., K.N.).
Koichi
K
Node
Department 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.).
Keiichi
K
Fukuda
D000818:Animals; D001696:Biomechanical Phenomena; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009210:Myofibrils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D018754:Ventricular Dysfunction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014741:Video Recording; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D019332:Endothelin-1; D000099163:Myosin Binding Protein C
ET‐1; HCM; MYBPC3; disease modeling; iPS cells