A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling

Autores
Camacho Londoño, Juan E.; Tian, Qinghai; Hammer, Karin; Schröder, Laura; Camacho Londoño, Julia; Reil, Jan C.; He, Tao; Oberhofer, Martin; Mannebach, Stefanie; Mathar, Ilka; Philipp, Stephan E.; Tabellion, Wiebke; Schweda, Frank; Dietrich, Alexander; Kaestner, Lars; Laufs, Ulrich; Birnbaumer, Lutz; Flockerzi, Veit; Freichel, Marc; Lipp, Peter
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aims: Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca2+ signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca2+ homeostasis in cardiomyocytes during fast cytosolic Ca2+ cycling and neurohumoral stimulation leading to hypertrophy is unknown. Methods and results: In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn2+-quench microfluorimetry, we identified a background Ca2+ entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca2+ concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca2+-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure. Conclusions: The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca2+ cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.
Fil: Camacho Londoño, Juan E.. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; Alemania
Fil: Tian, Qinghai. Institut fur Molekulare Zellbiologie; Alemania
Fil: Hammer, Karin. Institut fur Molekulare Zellbiologie; Alemania
Fil: Schröder, Laura. Institut fur Molekulare Zellbiologie; Alemania
Fil: Camacho Londoño, Julia. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Reil, Jan C.. Universitat des Saarlandes; Alemania
Fil: He, Tao. German Centre for Cardiovascular Research; Alemania. Research Unit Cardiac Epigenetics; Alemania. Tongji Hospital; China
Fil: Oberhofer, Martin. Institut fur Molekulare Zellbiologie; Alemania
Fil: Mannebach, Stefanie. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Mathar, Ilka. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Philipp, Stephan E.. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Tabellion, Wiebke. Institut fur Molekulare Zellbiologie; Alemania
Fil: Schweda, Frank. Universitat Regensburg; Alemania
Fil: Dietrich, Alexander. Walther-Straub-Institut fur Pharmakologie und Toxikologie; Alemania
Fil: Kaestner, Lars. Institut fur Molekulare Zellbiologie; Alemania
Fil: Laufs, Ulrich. Universitat des Saarlandes; Alemania
Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Transmembrane Signaling Group; Alemania
Fil: Flockerzi, Veit. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Freichel, Marc. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; Alemania
Fil: Lipp, Peter. Institut fur Molekulare Zellbiologie; Alemania
Materia
Calcium
Ion channels
Cardiac remodelling
Background Ca2+ entry
TRPC1/TRPC4
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/43532
Acceder
id CONICETDig_901851dbd218cf531f3d1a938d11acdc
oai_identifier_str oai:ri.conicet.gov.ar:11336/43532
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodellingCamacho Londoño, Juan E.Tian, QinghaiHammer, KarinSchröder, LauraCamacho Londoño, JuliaReil, Jan C.He, TaoOberhofer, MartinMannebach, StefanieMathar, IlkaPhilipp, Stephan E.Tabellion, WiebkeSchweda, FrankDietrich, AlexanderKaestner, LarsLaufs, UlrichBirnbaumer, LutzFlockerzi, VeitFreichel, MarcLipp, PeterCalciumIon channelsCardiac remodellingBackground Ca2+ entryTRPC1/TRPC4https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Aims: Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca2+ signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca2+ homeostasis in cardiomyocytes during fast cytosolic Ca2+ cycling and neurohumoral stimulation leading to hypertrophy is unknown. Methods and results: In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn2+-quench microfluorimetry, we identified a background Ca2+ entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca2+ concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca2+-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure. Conclusions: The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca2+ cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.Fil: Camacho Londoño, Juan E.. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; AlemaniaFil: Tian, Qinghai. Institut fur Molekulare Zellbiologie; AlemaniaFil: Hammer, Karin. Institut fur Molekulare Zellbiologie; AlemaniaFil: Schröder, Laura. Institut fur Molekulare Zellbiologie; AlemaniaFil: Camacho Londoño, Julia. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Reil, Jan C.. Universitat des Saarlandes; AlemaniaFil: He, Tao. German Centre for Cardiovascular Research; Alemania. Research Unit Cardiac Epigenetics; Alemania. Tongji Hospital; ChinaFil: Oberhofer, Martin. Institut fur Molekulare Zellbiologie; AlemaniaFil: Mannebach, Stefanie. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Mathar, Ilka. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Philipp, Stephan E.. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Tabellion, Wiebke. Institut fur Molekulare Zellbiologie; AlemaniaFil: Schweda, Frank. Universitat Regensburg; AlemaniaFil: Dietrich, Alexander. Walther-Straub-Institut fur Pharmakologie und Toxikologie; AlemaniaFil: Kaestner, Lars. Institut fur Molekulare Zellbiologie; AlemaniaFil: Laufs, Ulrich. Universitat des Saarlandes; AlemaniaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Transmembrane Signaling Group; AlemaniaFil: Flockerzi, Veit. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Freichel, Marc. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; AlemaniaFil: Lipp, Peter. Institut fur Molekulare Zellbiologie; AlemaniaOxford University Press2015-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/43532Camacho Londoño, Juan E.; Tian, Qinghai; Hammer, Karin; Schröder, Laura; Camacho Londoño, Julia; et al.; A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling; Oxford University Press; European Heart Journal; 36; 33; 9-2015; 2257-22660195-668XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1093/eurheartj/ehv250info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/eurheartj/article/36/33/2257/2466019info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:29:41Zoai:ri.conicet.gov.ar:11336/43532instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:29:42.175CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
title A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
spellingShingle A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
Camacho Londoño, Juan E.
Calcium
Ion channels
Cardiac remodelling
Background Ca2+ entry
TRPC1/TRPC4
title_short A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
title_full A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
title_fullStr A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
title_full_unstemmed A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
title_sort A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
dc.creator.none.fl_str_mv Camacho Londoño, Juan E.
Tian, Qinghai
Hammer, Karin
Schröder, Laura
Camacho Londoño, Julia
Reil, Jan C.
He, Tao
Oberhofer, Martin
Mannebach, Stefanie
Mathar, Ilka
Philipp, Stephan E.
Tabellion, Wiebke
Schweda, Frank
Dietrich, Alexander
Kaestner, Lars
Laufs, Ulrich
Birnbaumer, Lutz
Flockerzi, Veit
Freichel, Marc
Lipp, Peter
author Camacho Londoño, Juan E.
author_facet Camacho Londoño, Juan E.
Tian, Qinghai
Hammer, Karin
Schröder, Laura
Camacho Londoño, Julia
Reil, Jan C.
He, Tao
Oberhofer, Martin
Mannebach, Stefanie
Mathar, Ilka
Philipp, Stephan E.
Tabellion, Wiebke
Schweda, Frank
Dietrich, Alexander
Kaestner, Lars
Laufs, Ulrich
Birnbaumer, Lutz
Flockerzi, Veit
Freichel, Marc
Lipp, Peter
author_role author
author2 Tian, Qinghai
Hammer, Karin
Schröder, Laura
Camacho Londoño, Julia
Reil, Jan C.
He, Tao
Oberhofer, Martin
Mannebach, Stefanie
Mathar, Ilka
Philipp, Stephan E.
Tabellion, Wiebke
Schweda, Frank
Dietrich, Alexander
Kaestner, Lars
Laufs, Ulrich
Birnbaumer, Lutz
Flockerzi, Veit
Freichel, Marc
Lipp, Peter
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Calcium
Ion channels
Cardiac remodelling
Background Ca2+ entry
TRPC1/TRPC4
topic Calcium
Ion channels
Cardiac remodelling
Background Ca2+ entry
TRPC1/TRPC4
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Aims: Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca2+ signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca2+ homeostasis in cardiomyocytes during fast cytosolic Ca2+ cycling and neurohumoral stimulation leading to hypertrophy is unknown. Methods and results: In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn2+-quench microfluorimetry, we identified a background Ca2+ entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca2+ concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca2+-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure. Conclusions: The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca2+ cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.
Fil: Camacho Londoño, Juan E.. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; Alemania
Fil: Tian, Qinghai. Institut fur Molekulare Zellbiologie; Alemania
Fil: Hammer, Karin. Institut fur Molekulare Zellbiologie; Alemania
Fil: Schröder, Laura. Institut fur Molekulare Zellbiologie; Alemania
Fil: Camacho Londoño, Julia. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Reil, Jan C.. Universitat des Saarlandes; Alemania
Fil: He, Tao. German Centre for Cardiovascular Research; Alemania. Research Unit Cardiac Epigenetics; Alemania. Tongji Hospital; China
Fil: Oberhofer, Martin. Institut fur Molekulare Zellbiologie; Alemania
Fil: Mannebach, Stefanie. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Mathar, Ilka. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Philipp, Stephan E.. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Tabellion, Wiebke. Institut fur Molekulare Zellbiologie; Alemania
Fil: Schweda, Frank. Universitat Regensburg; Alemania
Fil: Dietrich, Alexander. Walther-Straub-Institut fur Pharmakologie und Toxikologie; Alemania
Fil: Kaestner, Lars. Institut fur Molekulare Zellbiologie; Alemania
Fil: Laufs, Ulrich. Universitat des Saarlandes; Alemania
Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Transmembrane Signaling Group; Alemania
Fil: Flockerzi, Veit. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania
Fil: Freichel, Marc. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; Alemania
Fil: Lipp, Peter. Institut fur Molekulare Zellbiologie; Alemania
description Aims: Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca2+ signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca2+ homeostasis in cardiomyocytes during fast cytosolic Ca2+ cycling and neurohumoral stimulation leading to hypertrophy is unknown. Methods and results: In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn2+-quench microfluorimetry, we identified a background Ca2+ entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca2+ concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca2+-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure. Conclusions: The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca2+ cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.
publishDate 2015
dc.date.none.fl_str_mv 2015-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/43532
Camacho Londoño, Juan E.; Tian, Qinghai; Hammer, Karin; Schröder, Laura; Camacho Londoño, Julia; et al.; A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling; Oxford University Press; European Heart Journal; 36; 33; 9-2015; 2257-2266
0195-668X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/43532
identifier_str_mv Camacho Londoño, Juan E.; Tian, Qinghai; Hammer, Karin; Schröder, Laura; Camacho Londoño, Julia; et al.; A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling; Oxford University Press; European Heart Journal; 36; 33; 9-2015; 2257-2266
0195-668X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/eurheartj/ehv250
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/eurheartj/article/36/33/2257/2466019
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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