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dc.contributor.author
Seo, Kinya
dc.contributor.author
Rainer, Peter P.
dc.contributor.author
Shalkey Hahn, Virginia
dc.contributor.author
Lee, Dong-ik
dc.contributor.author
Jo, Su-Hyun
dc.contributor.author
Andersen, Asger
dc.contributor.author
Liu, Ting
dc.contributor.author
Xu, Xiaoping
dc.contributor.author
Willette, Robert N.
dc.contributor.author
Lepore, John J.
dc.contributor.author
Marino, Joseph P.
dc.contributor.author
Birnbaumer, Lutz
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dc.contributor.author
Schnackenberg, Christine G.
dc.contributor.author
Kass, David A.
dc.date.available
2020-03-06T16:27:27Z
dc.date.issued
2014-01-28
dc.identifier.citation
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
dc.identifier.issn
0027-8424
dc.identifier.uri
http://hdl.handle.net/11336/98932
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
National Academy of Sciences
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
ION CHANNELS
dc.subject
CALCIUM
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NUCLEAR FACTOR OF ACTIVATED
dc.subject
T CELLS
dc.subject.classification
Bioquímica y Biología Molecular
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-10-28T18:26:20Z
dc.identifier.eissn
1091-6490
dc.journal.volume
111
dc.journal.number
4
dc.journal.pagination
1551-1556
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington
dc.description.fil
Fil: Seo, Kinya. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
dc.description.fil
Fil: Rainer, Peter P.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos. Medical University of Graz. Department of Medicine; Austria
dc.description.fil
Fil: Shalkey Hahn, Virginia. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
dc.description.fil
Fil: Lee, Dong-ik. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
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Fil: Jo, Su-Hyun. Kangwon National University School of Medicine; Corea del Sur. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
dc.description.fil
Fil: Andersen, Asger. Aarhus University Hospital. Department of Cardiology; Dinamarca
dc.description.fil
Fil: Liu, Ting. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
dc.description.fil
Fil: Xu, Xiaoping. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
dc.description.fil
Fil: Willette, Robert N.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
dc.description.fil
Fil: Lepore, John J.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
dc.description.fil
Fil: Marino, Joseph P.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
dc.description.fil
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
dc.description.fil
Fil: Schnackenberg, Christine G.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados Unidos
dc.description.fil
Fil: Kass, David A.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos
dc.journal.title
Proceedings of the National Academy of Sciences of The United States of America
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/111/4/1551
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/doi.org/10.1073/pnas.1308963111
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