Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Autores
Seo, Kinya; Rainer, Peter P.; Shalkey Hahn, Virginia; Lee, Dong-ik; Jo, Su-Hyun; Andersen, Asger; Liu, Ting; Xu, Xiaoping; Willette, Robert N.; Lepore, John J.; Marino, Joseph P.; Birnbaumer, Lutz; Schnackenberg, Christine G.; Kass, David A.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chronic neurohormonal and mechanical stresses are central fea-tures of heart disease. Increasing evidence supports a role forthe transient receptor potential canonical channels TRPC3 andTRPC6 in this pathophysiology. Channel expression for both is nor-mally very low but is increased by cardiac disease, and geneticgain- or loss-of-function studies support contributions to hypertro-phy and dysfunction. Selective small-molecule inhibitors remainscarce, and none target both channels, which may be useful giventhe high homology among them and evidence of redundant sig-naling. Here we tested selective TRPC3/6 antagonists (GSK2332255Band GSK2833503A; IC50,3–21 nM against TRPC3 and TRPC6) andfound dose-dependent blockade of cell hypertrophy signaling trig-gered by angiotensin II or endothelin-1 in HEK293T cells as well as inneonatal and adult cardiac myocytes. In vivo efficacy in mice andrats was greatly limited by rapid metabolism and high protein bind-ing, although antifibrotic effects with pressure overload were ob-served. Intriguingly, although gene deletion of TRPC3 or TRPC6alone did not protect against hypertrophy or dysfunction frompressure overload, combined deletion was protective, support-ing the value of dual inhibition. Further development of thispharmaceutical class may yield a useful therapeutic agent forheart disease management.
Fil: Seo, Kinya. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Rainer, Peter P.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos. Medical University of Graz. Department of Medicine; Austria
Fil: Shalkey Hahn, Virginia. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Lee, Dong-ik. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Jo, Su-Hyun. Kangwon National University School of Medicine; Corea del Sur. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Andersen, Asger. Aarhus University Hospital. Department of Cardiology; Dinamarca
Fil: Liu, Ting. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Xu, Xiaoping. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Willette, Robert N.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Lepore, John J.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Marino, Joseph P.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Birnbaumer, Lutz. ational Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Schnackenberg, Christine G.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Kass, David A.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Materia
ION CHANNELS
CALCIUM
NUCLEAR FACTOR OF ACTIVATED
T CELLS
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:11336/98932
Acceder
id CONICETDig_449a7211017cc39c96f2edefb402c513
oai_identifier_str oai:ri.conicet.gov.ar:11336/98932
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophySeo, KinyaRainer, Peter P.Shalkey Hahn, VirginiaLee, Dong-ikJo, Su-HyunAndersen, AsgerLiu, TingXu, XiaopingWillette, Robert N.Lepore, John J.Marino, Joseph P.Birnbaumer, LutzSchnackenberg, Christine G.Kass, David A.ION CHANNELSCALCIUMNUCLEAR FACTOR OF ACTIVATEDT CELLShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Chronic neurohormonal and mechanical stresses are central fea-tures of heart disease. Increasing evidence supports a role forthe transient receptor potential canonical channels TRPC3 andTRPC6 in this pathophysiology. Channel expression for both is nor-mally very low but is increased by cardiac disease, and geneticgain- or loss-of-function studies support contributions to hypertro-phy and dysfunction. Selective small-molecule inhibitors remainscarce, and none target both channels, which may be useful giventhe high homology among them and evidence of redundant sig-naling. Here we tested selective TRPC3/6 antagonists (GSK2332255Band GSK2833503A; IC50,3–21 nM against TRPC3 and TRPC6) andfound dose-dependent blockade of cell hypertrophy signaling trig-gered by angiotensin II or endothelin-1 in HEK293T cells as well as inneonatal and adult cardiac myocytes. In vivo efficacy in mice andrats was greatly limited by rapid metabolism and high protein bind-ing, although antifibrotic effects with pressure overload were ob-served. Intriguingly, although gene deletion of TRPC3 or TRPC6alone did not protect against hypertrophy or dysfunction frompressure overload, combined deletion was protective, support-ing the value of dual inhibition. Further development of thispharmaceutical class may yield a useful therapeutic agent forheart disease management.Fil: Seo, Kinya. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Rainer, Peter P.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos. Medical University of Graz. Department of Medicine; AustriaFil: Shalkey Hahn, Virginia. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Lee, Dong-ik. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Jo, Su-Hyun. Kangwon National University School of Medicine; Corea del Sur. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Andersen, Asger. Aarhus University Hospital. Department of Cardiology; DinamarcaFil: Liu, Ting. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Xu, Xiaoping. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Willette, Robert N.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Lepore, John J.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Marino, Joseph P.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Birnbaumer, Lutz. ational Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Schnackenberg, Christine G.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Kass, David A.. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosNational Academy of Sciences2014-01-28info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/98932Seo, Kinya; Rainer, Peter P.; Shalkey Hahn, Virginia; Lee, Dong-ik; Jo, Su-Hyun; et al.; Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 111; 4; 28-1-2014; 1551-15560027-84241091-6490CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/111/4/1551info:eu-repo/semantics/altIdentifier/doi/doi.org/10.1073/pnas.1308963111info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:38:36Zoai:ri.conicet.gov.ar:11336/98932instacron: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:34982025-09-29 09:38:37.036CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
title Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
spellingShingle Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
Seo, Kinya
ION CHANNELS
CALCIUM
NUCLEAR FACTOR OF ACTIVATED
T CELLS
title_short Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
title_full Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
title_fullStr Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
title_full_unstemmed Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
title_sort Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
dc.creator.none.fl_str_mv Seo, Kinya
Rainer, Peter P.
Shalkey Hahn, Virginia
Lee, Dong-ik
Jo, Su-Hyun
Andersen, Asger
Liu, Ting
Xu, Xiaoping
Willette, Robert N.
Lepore, John J.
Marino, Joseph P.
Birnbaumer, Lutz
Schnackenberg, Christine G.
Kass, David A.
author Seo, Kinya
author_facet Seo, Kinya
Rainer, Peter P.
Shalkey Hahn, Virginia
Lee, Dong-ik
Jo, Su-Hyun
Andersen, Asger
Liu, Ting
Xu, Xiaoping
Willette, Robert N.
Lepore, John J.
Marino, Joseph P.
Birnbaumer, Lutz
Schnackenberg, Christine G.
Kass, David A.
author_role author
author2 Rainer, Peter P.
Shalkey Hahn, Virginia
Lee, Dong-ik
Jo, Su-Hyun
Andersen, Asger
Liu, Ting
Xu, Xiaoping
Willette, Robert N.
Lepore, John J.
Marino, Joseph P.
Birnbaumer, Lutz
Schnackenberg, Christine G.
Kass, David A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ION CHANNELS
CALCIUM
NUCLEAR FACTOR OF ACTIVATED
T CELLS
topic ION CHANNELS
CALCIUM
NUCLEAR FACTOR OF ACTIVATED
T CELLS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Chronic neurohormonal and mechanical stresses are central fea-tures of heart disease. Increasing evidence supports a role forthe transient receptor potential canonical channels TRPC3 andTRPC6 in this pathophysiology. Channel expression for both is nor-mally very low but is increased by cardiac disease, and geneticgain- or loss-of-function studies support contributions to hypertro-phy and dysfunction. Selective small-molecule inhibitors remainscarce, and none target both channels, which may be useful giventhe high homology among them and evidence of redundant sig-naling. Here we tested selective TRPC3/6 antagonists (GSK2332255Band GSK2833503A; IC50,3–21 nM against TRPC3 and TRPC6) andfound dose-dependent blockade of cell hypertrophy signaling trig-gered by angiotensin II or endothelin-1 in HEK293T cells as well as inneonatal and adult cardiac myocytes. In vivo efficacy in mice andrats was greatly limited by rapid metabolism and high protein bind-ing, although antifibrotic effects with pressure overload were ob-served. Intriguingly, although gene deletion of TRPC3 or TRPC6alone did not protect against hypertrophy or dysfunction frompressure overload, combined deletion was protective, support-ing the value of dual inhibition. Further development of thispharmaceutical class may yield a useful therapeutic agent forheart disease management.
Fil: Seo, Kinya. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Rainer, Peter P.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos. Medical University of Graz. Department of Medicine; Austria
Fil: Shalkey Hahn, Virginia. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Lee, Dong-ik. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Jo, Su-Hyun. Kangwon National University School of Medicine; Corea del Sur. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Andersen, Asger. Aarhus University Hospital. Department of Cardiology; Dinamarca
Fil: Liu, Ting. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
Fil: Xu, Xiaoping. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Willette, Robert N.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Lepore, John J.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Marino, Joseph P.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Birnbaumer, Lutz. ational Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Schnackenberg, Christine G.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
Fil: Kass, David A.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
description Chronic neurohormonal and mechanical stresses are central fea-tures of heart disease. Increasing evidence supports a role forthe transient receptor potential canonical channels TRPC3 andTRPC6 in this pathophysiology. Channel expression for both is nor-mally very low but is increased by cardiac disease, and geneticgain- or loss-of-function studies support contributions to hypertro-phy and dysfunction. Selective small-molecule inhibitors remainscarce, and none target both channels, which may be useful giventhe high homology among them and evidence of redundant sig-naling. Here we tested selective TRPC3/6 antagonists (GSK2332255Band GSK2833503A; IC50,3–21 nM against TRPC3 and TRPC6) andfound dose-dependent blockade of cell hypertrophy signaling trig-gered by angiotensin II or endothelin-1 in HEK293T cells as well as inneonatal and adult cardiac myocytes. In vivo efficacy in mice andrats was greatly limited by rapid metabolism and high protein bind-ing, although antifibrotic effects with pressure overload were ob-served. Intriguingly, although gene deletion of TRPC3 or TRPC6alone did not protect against hypertrophy or dysfunction frompressure overload, combined deletion was protective, support-ing the value of dual inhibition. Further development of thispharmaceutical class may yield a useful therapeutic agent forheart disease management.
publishDate 2014
dc.date.none.fl_str_mv 2014-01-28
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/11336/98932
Seo, Kinya; Rainer, Peter P.; Shalkey Hahn, Virginia; Lee, Dong-ik; Jo, Su-Hyun; et al.; Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 111; 4; 28-1-2014; 1551-1556
0027-8424
1091-6490
CONICET Digital
CONICET
url http://hdl.handle.net/11336/98932
identifier_str_mv Seo, Kinya; Rainer, Peter P.; Shalkey Hahn, Virginia; Lee, Dong-ik; Jo, Su-Hyun; et al.; Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 111; 4; 28-1-2014; 1551-1556
0027-8424
1091-6490
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/111/4/1551
info:eu-repo/semantics/altIdentifier/doi/doi.org/10.1073/pnas.1308963111
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 National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
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 13.070432

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