Endothelin‐1 Induces Myofibrillar Disarray and Contractile Vector Variability in Hypertrophic Cardiomyopathy–Induced Pluripotent Stem Cell–Derived Cardiomyocytes

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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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Most cited references 38

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Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy.

Yan Dai, Lindsay Plank, Kristy S. Parsons … (2004)

Calcineurin (PP2B) is a calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the nucleus through the dephosphorylation and translocation of nuclear factor of activated T cell (NFAT) transcription factors. Whereas calcineurin-NFAT signaling has been implicated in regulating the hypertrophic growth of the myocardium, considerable controversy persists as to its role in maintaining versus initiating hypertrophy, its role in pathological versus physiological hypertrophy, and its role in heart failure. To address these issues, NFAT-luciferase reporter transgenic mice were generated and characterized. These mice showed robust and calcineurin-specific activation in the heart that was inhibited with cyclosporin A. In the adult heart, NFAT-luciferase activity was upregulated in a delayed, but sustained manner throughout eight weeks of pathological cardiac hypertrophy induced by pressure-overload, or more dramatically following myocardial infarction-induced heart failure. In contrast, physiological hypertrophy as produced in two separate models of exercise training failed to show significant calcineurin-NFAT coupling in the heart at multiple time points, despite measurable increases in heart to body weight ratios. Moreover, stimulation of hypertrophy with growth hormone-insulin-like growth factor-1 (GH-IGF-1) failed to activate calcineurin-NFAT signaling in the heart or in culture, despite hypertrophy, activation of Akt, and activation of p70 S6K. Calcineurin Abeta gene-targeted mice also showed a normal hypertrophic response after GH-IGF-1 infusion. Lastly, exercise- or GH-IGF-1-induced cardiac growth failed to show induction of hypertrophic marker gene expression compared with pressure-overloaded animals. Although a direct cause-and-effect relationship between NFAT-luciferase activity and pathological hypertrophy was not proven here, our results support the hypothesis that separable signaling pathways regulate pathological versus physiological hypertrophic growth of the myocardium, with calcineurin-NFAT potentially serving a regulatory role that is more specialized for maladaptive hypertrophy and heart failure.

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Endothelin system: the double-edged sword in health and disease.

M Yanagisawa, M. Kędzierski (2000)

The endothelin system consists of two G-protein-coupled receptors, three peptide ligands, and two activating peptidases. Its pharmacological complexity is reflected by the diverse expression pattern of endothelin system components, which have a variety of physiological and pathophysiological roles. In the vessels, the endothelin system has a basal vasoconstricting role and participates in the development of diseases such as hypertension, atherosclerosis, and vasospasm after subarachnoid hemorrhage. In the heart, the endothelin system affects inotropy and chronotropy, and it mediates cardiac hypertrophy and remodeling in congestive heart failure. In the lungs, the endothelin system regulates the tone of airways and blood vessels, and it is involved in the development of pulmonary hypertension. In the kidney, it controls water and sodium excretion and acid-base balance, and it participates in acute and chronic renal failure. In the brain, the endothelin system modulates cardiorespiratory centers and the release of hormones. More advanced functional analysis of the endothelin system awaits not only additional pharmacological studies using highly specific endothelin antagonists but also the generation of genetically altered rodent models with conditional loss-of-function and gain-of-function manipulations.

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Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction.

Michelle Michels, Olle ten Cate, Lucie Carrier … (2009)

Mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), are a frequent cause of familial hypertrophic cardiomyopathy. In the present study, we investigated whether protein composition and function of the sarcomere are altered in a homogeneous familial hypertrophic cardiomyopathy patient group with frameshift mutations in MYBPC3 (MYBPC3(mut)). Comparisons were made between cardiac samples from MYBPC3 mutant carriers (c.2373dupG, n=7; c.2864_2865delCT, n=4) and nonfailing donors (n=13). Western blots with the use of antibodies directed against cMyBP-C did not reveal truncated cMyBP-C in MYBPC3(mut). Protein expression of cMyBP-C was significantly reduced in MYBPC3(mut) by 33+/-5%. Cardiac MyBP-C phosphorylation in MYBPC3(mut) samples was similar to the values in donor samples, whereas the phosphorylation status of cardiac troponin I was reduced by 84+/-5%, indicating divergent phosphorylation of the 2 main contractile target proteins of the beta-adrenergic pathway. Force measurements in mechanically isolated Triton-permeabilized cardiomyocytes demonstrated a decrease in maximal force per cross-sectional area of the myocytes in MYBPC3(mut) (20.2+/-2.7 kN/m(2)) compared with donor (34.5+/-1.1 kN/m(2)). Moreover, Ca(2+) sensitivity was higher in MYBPC3(mut) (pCa(50)=5.62+/-0.04) than in donor (pCa(50)=5.54+/-0.02), consistent with reduced cardiac troponin I phosphorylation. Treatment with exogenous protein kinase A, to mimic beta-adrenergic stimulation, did not correct reduced maximal force but abolished the initial difference in Ca(2+) sensitivity between MYBPC3(mut) (pCa(50)=5.46+/-0.03) and donor (pCa(50)=5.48+/-0.02). Frameshift MYBPC3 mutations cause haploinsufficiency, deranged phosphorylation of contractile proteins, and reduced maximal force-generating capacity of cardiomyocytes. The enhanced Ca(2+) sensitivity in MYBPC3(mut) is due to hypophosphorylation of troponin I secondary to mutation-induced dysfunction.

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Author and article information

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (hwp): ahaoa

Journal ID (publisher-id): jah3

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: Blackwell Publishing Ltd

ISSN (Electronic): 2047-9980

Publication date Collection: December 2014

Publication date (Electronic): 11 November 2014

Volume: 3

Issue: 6

Electronic Location Identifier: e001263

Affiliations

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.)

Department of Bio‐informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (S.O., T.F.)

Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.A., A.K.)

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.)

Author notes

Correspondence to: Shinsuke Yuasa, MD, PhD, Department of Cardiology, Keio University school of Medicine, 35‐Shinanomachi Shinjuku‐ku, Tokyo, Japan, 160‐8582. E‐mail: yuasa@ 123456a8.keio.jp

Accompanying Video clips S1 and S2 are available at http://jaha.ahajournals.org/content/3/5/e001263/suppl/DC1

Article

Publisher ID: jah3730

DOI: 10.1161/JAHA.114.001263

PMC ID: 4338713

PubMed ID: 25389285

SO-VID: 7a585af1-166d-4dd9-b224-168781303480

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Endothelin‐1 Induces Myofibrillar Disarray and Contractile Vector Variability in Hypertrophic Cardiomyopathy–Induced Pluripotent Stem Cell–Derived Cardiomyocytes

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Abstract

Background

Methods and Results

Conclusions

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Cardiovascular Innovations and Applications

Most cited references 38

Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy.

Endothelin system: the double-edged sword in health and disease.

Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction.

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