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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/98932
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oai:ri.conicet.gov.ar:11336/98932 |
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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 Técnicas2025-09-03T09:46:58Zoai: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:34982025-09-03 09:46:58.914CONICET 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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1842268828794355712 |
score |
13.13397 |