Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart

Willemijn Van Eldik, Brigit Den Adel, Jantine J. Monshouwer-Kloots, Daniela Salvatori, Saskia Maas, Ingeborg Van Der Made, Esther E. Creemers, Derk Frank, Norbert Frey, Nicky Boontje, Jolanda Van Der Velden, Paul Steendijk, Christine Mummery, Robert Passier, Abdelaziz Beqqali*

*Corresponding author for this work

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Abstract

Aims: The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/ transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease.

Methods and results: Mice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb post-natally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers.

Conclusion: This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation.

Original languageEnglish
Article numbere0189139
JournalPLoS ONE
Volume12
Issue number12
DOIs
Publication statusPublished - 1 Dec 2017
Externally publishedYes

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cardiomyopathy
Cardiomyopathies
actin
Actins
heart
hypertrophy
genetically modified organisms
Transgenic Mice
Sarcomeres
Protein Isoforms
sarcomeres
Cardiomegaly
Proteins
Heart Atria
fibrosis
proteins
Atrial Fibrillation
mice
Fibrosis
protein isoforms

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Van Eldik, W., Den Adel, B., Monshouwer-Kloots, J. J., Salvatori, D., Maas, S., Van Der Made, I., ... Beqqali, A. (2017). Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart. PLoS ONE, 12(12), [e0189139]. https://doi.org/10.1371/journal.pone.0189139
Van Eldik, Willemijn ; Den Adel, Brigit ; Monshouwer-Kloots, Jantine J. ; Salvatori, Daniela ; Maas, Saskia ; Van Der Made, Ingeborg ; Creemers, Esther E. ; Frank, Derk ; Frey, Norbert ; Boontje, Nicky ; Van Der Velden, Jolanda ; Steendijk, Paul ; Mummery, Christine ; Passier, Robert ; Beqqali, Abdelaziz. / Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart. In: PLoS ONE. 2017 ; Vol. 12, No. 12.
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title = "Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart",
abstract = "Aims: The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/ transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease.Methods and results: Mice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb post-natally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers.Conclusion: This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation.",
author = "{Van Eldik}, Willemijn and {Den Adel}, Brigit and Monshouwer-Kloots, {Jantine J.} and Daniela Salvatori and Saskia Maas and {Van Der Made}, Ingeborg and Creemers, {Esther E.} and Derk Frank and Norbert Frey and Nicky Boontje and {Van Der Velden}, Jolanda and Paul Steendijk and Christine Mummery and Robert Passier and Abdelaziz Beqqali",
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Van Eldik, W, Den Adel, B, Monshouwer-Kloots, JJ, Salvatori, D, Maas, S, Van Der Made, I, Creemers, EE, Frank, D, Frey, N, Boontje, N, Van Der Velden, J, Steendijk, P, Mummery, C, Passier, R & Beqqali, A 2017, 'Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart', PLoS ONE, vol. 12, no. 12, e0189139. https://doi.org/10.1371/journal.pone.0189139

Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart. / Van Eldik, Willemijn; Den Adel, Brigit; Monshouwer-Kloots, Jantine J.; Salvatori, Daniela; Maas, Saskia; Van Der Made, Ingeborg; Creemers, Esther E.; Frank, Derk; Frey, Norbert; Boontje, Nicky; Van Der Velden, Jolanda; Steendijk, Paul; Mummery, Christine; Passier, Robert; Beqqali, Abdelaziz.

In: PLoS ONE, Vol. 12, No. 12, e0189139, 01.12.2017.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart

AU - Van Eldik, Willemijn

AU - Den Adel, Brigit

AU - Monshouwer-Kloots, Jantine J.

AU - Salvatori, Daniela

AU - Maas, Saskia

AU - Van Der Made, Ingeborg

AU - Creemers, Esther E.

AU - Frank, Derk

AU - Frey, Norbert

AU - Boontje, Nicky

AU - Van Der Velden, Jolanda

AU - Steendijk, Paul

AU - Mummery, Christine

AU - Passier, Robert

AU - Beqqali, Abdelaziz

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Aims: The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/ transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease.Methods and results: Mice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb post-natally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers.Conclusion: This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation.

AB - Aims: The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/ transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease.Methods and results: Mice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb post-natally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers.Conclusion: This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation.

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Van Eldik W, Den Adel B, Monshouwer-Kloots JJ, Salvatori D, Maas S, Van Der Made I et al. Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart. PLoS ONE. 2017 Dec 1;12(12). e0189139. https://doi.org/10.1371/journal.pone.0189139