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Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations

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Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations. / Sequeira, Vasco; Wijnker, Paul J M; Nijenkamp, Louise L A M; Kuster, Diederik W D; Najafi, Aref; Witjas-Paalberends, E Rosalie; Regan, Jessica A; Boontje, Nicky; Ten Cate, Folkert J; Germans, Tjeerd; Carrier, Lucie; Sadayappan, Sakthivel; van Slegtenhorst, Marjon A; Zaremba, Ruud; Foster, D Brian; Murphy, Anne M; Poggesi, Corrado; Dos Remedios, Cris; Stienen, Ger J M; Ho, Carolyn Y; Michels, Michelle; van der Velden, Jolanda.

In: CIRC RES, Vol. 112, No. 11, 24.05.2013, p. 1491-505.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sequeira, V, Wijnker, PJM, Nijenkamp, LLAM, Kuster, DWD, Najafi, A, Witjas-Paalberends, ER, Regan, JA, Boontje, N, Ten Cate, FJ, Germans, T, Carrier, L, Sadayappan, S, van Slegtenhorst, MA, Zaremba, R, Foster, DB, Murphy, AM, Poggesi, C, Dos Remedios, C, Stienen, GJM, Ho, CY, Michels, M & van der Velden, J 2013, 'Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations', CIRC RES, vol. 112, no. 11, pp. 1491-505. https://doi.org/10.1161/CIRCRESAHA.111.300436

APA

Sequeira, V., Wijnker, P. J. M., Nijenkamp, L. L. A. M., Kuster, D. W. D., Najafi, A., Witjas-Paalberends, E. R., Regan, J. A., Boontje, N., Ten Cate, F. J., Germans, T., Carrier, L., Sadayappan, S., van Slegtenhorst, M. A., Zaremba, R., Foster, D. B., Murphy, A. M., Poggesi, C., Dos Remedios, C., Stienen, G. J. M., ... van der Velden, J. (2013). Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations. CIRC RES, 112(11), 1491-505. https://doi.org/10.1161/CIRCRESAHA.111.300436

Vancouver

Sequeira V, Wijnker PJM, Nijenkamp LLAM, Kuster DWD, Najafi A, Witjas-Paalberends ER et al. Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations. CIRC RES. 2013 May 24;112(11):1491-505. https://doi.org/10.1161/CIRCRESAHA.111.300436

Bibtex

@article{1cff7e15b229467e831206ef36277f26,
title = "Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations",
abstract = "RATIONALE: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce.OBJECTIVE: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins.METHODS AND RESULTS: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values.CONCLUSIONS: High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.",
keywords = "Adolescent, Adult, Aged, Animals, Calcium, Cardiac Myosins, Cardiomyopathy, Hypertrophic, Carrier Proteins, Cyclic AMP-Dependent Protein Kinases, Female, Humans, Isometric Contraction, MAP Kinase Kinase Kinases, Male, Mice, Middle Aged, Mutation, Missense, Myocardial Contraction, Myocardium, Myofibrils, Myosin Heavy Chains, Phosphorylation, Sarcomeres, Tropomyosin, Troponin T, Young Adult",
author = "Vasco Sequeira and Wijnker, {Paul J M} and Nijenkamp, {Louise L A M} and Kuster, {Diederik W D} and Aref Najafi and Witjas-Paalberends, {E Rosalie} and Regan, {Jessica A} and Nicky Boontje and {Ten Cate}, {Folkert J} and Tjeerd Germans and Lucie Carrier and Sakthivel Sadayappan and {van Slegtenhorst}, {Marjon A} and Ruud Zaremba and Foster, {D Brian} and Murphy, {Anne M} and Corrado Poggesi and {Dos Remedios}, Cris and Stienen, {Ger J M} and Ho, {Carolyn Y} and Michelle Michels and {van der Velden}, Jolanda",
note = "Wijnker f{\"u}r: Vrije Univ Amsterdam Med Ctr, Inst Cardiovasc Res, Physiol Lab, NL-1081 BT Amsterdam, Netherlands",
year = "2013",
month = may,
day = "24",
doi = "10.1161/CIRCRESAHA.111.300436",
language = "English",
volume = "112",
pages = "1491--505",
journal = "CIRC RES",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

RIS

TY - JOUR

T1 - Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations

AU - Sequeira, Vasco

AU - Wijnker, Paul J M

AU - Nijenkamp, Louise L A M

AU - Kuster, Diederik W D

AU - Najafi, Aref

AU - Witjas-Paalberends, E Rosalie

AU - Regan, Jessica A

AU - Boontje, Nicky

AU - Ten Cate, Folkert J

AU - Germans, Tjeerd

AU - Carrier, Lucie

AU - Sadayappan, Sakthivel

AU - van Slegtenhorst, Marjon A

AU - Zaremba, Ruud

AU - Foster, D Brian

AU - Murphy, Anne M

AU - Poggesi, Corrado

AU - Dos Remedios, Cris

AU - Stienen, Ger J M

AU - Ho, Carolyn Y

AU - Michels, Michelle

AU - van der Velden, Jolanda

N1 - Wijnker für: Vrije Univ Amsterdam Med Ctr, Inst Cardiovasc Res, Physiol Lab, NL-1081 BT Amsterdam, Netherlands

PY - 2013/5/24

Y1 - 2013/5/24

N2 - RATIONALE: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce.OBJECTIVE: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins.METHODS AND RESULTS: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values.CONCLUSIONS: High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.

AB - RATIONALE: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce.OBJECTIVE: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins.METHODS AND RESULTS: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values.CONCLUSIONS: High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.

KW - Adolescent

KW - Adult

KW - Aged

KW - Animals

KW - Calcium

KW - Cardiac Myosins

KW - Cardiomyopathy, Hypertrophic

KW - Carrier Proteins

KW - Cyclic AMP-Dependent Protein Kinases

KW - Female

KW - Humans

KW - Isometric Contraction

KW - MAP Kinase Kinase Kinases

KW - Male

KW - Mice

KW - Middle Aged

KW - Mutation, Missense

KW - Myocardial Contraction

KW - Myocardium

KW - Myofibrils

KW - Myosin Heavy Chains

KW - Phosphorylation

KW - Sarcomeres

KW - Tropomyosin

KW - Troponin T

KW - Young Adult

U2 - 10.1161/CIRCRESAHA.111.300436

DO - 10.1161/CIRCRESAHA.111.300436

M3 - SCORING: Journal article

C2 - 23508784

VL - 112

SP - 1491

EP - 1505

JO - CIRC RES

JF - CIRC RES

SN - 0009-7330

IS - 11

ER -