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Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability

Authordc.contributor.authorPedrozo Cibils, Zully 
Authordc.contributor.authorCriollo Céspedes, Alfredo 
Authordc.contributor.authorBattiprolu, Pavan K. 
Authordc.contributor.authorMorales, Cyndi R. 
Authordc.contributor.authorContreras Ferrat, Ariel Eduardo 
Authordc.contributor.authorFernández, Carolina 
Authordc.contributor.authorJiang, Nan 
Authordc.contributor.authorLuo, Xiang 
Authordc.contributor.authorCaplan, Michael J. 
Authordc.contributor.authorSomlo, Stefan 
Authordc.contributor.authorRothermel, Beverly A. 
Authordc.contributor.authorGillette, Thomas G. 
Authordc.contributor.authorLavandero González, Sergio 
Authordc.contributor.authorHill, Joseph A. 
Admission datedc.date.accessioned2016-04-12T18:15:05Z
Available datedc.date.available2016-04-12T18:15:05Z
Publication datedc.date.issued2015
Cita de ítemdc.identifier.citationCirculation Volumen: 131 Número: 24 Páginas: 2131-2142 (2015)en_US
Identifierdc.identifier.otherDOI: 10.1161/CIRCULATIONAHA.114.013537
Identifierdc.identifier.urihttp://repositorio.uchile.cl/handle/2250/137732
General notedc.descriptionArtículo de publicación ISIen_US
Abstractdc.description.abstractBackground-L-type calcium channel activity is critical to afterload-induced hypertrophic growth of the heart. However, the mechanisms governing mechanical stress-induced activation of L-type calcium channel activity are obscure. Polycystin-1 (PC-1) is a G protein-coupled receptor-like protein that functions as a mechanosensor in a variety of cell types and is present in cardiomyocytes. Methods and Results-We subjected neonatal rat ventricular myocytes to mechanical stretch by exposing them to hypoosmotic medium or cyclic mechanical stretch, triggering cell growth in a manner dependent on L-type calcium channel activity. RNAi-dependent knockdown of PC-1 blocked this hypertrophy. Overexpression of a C-terminal fragment of PC-1 was sufficient to trigger neonatal rat ventricular myocyte hypertrophy. Exposing neonatal rat ventricular myocytes to hypo-osmotic medium resulted in an increase in alpha 1C protein levels, a response that was prevented by PC-1 knockdown. MG132, a proteasomal inhibitor, rescued PC-1 knockdown-dependent declines in alpha 1C protein. To test this in vivo, we engineered mice harboring conditional silencing of PC-1 selectively in cardiomyocytes (PC-1 knockout) and subjected them to mechanical stress in vivo (transverse aortic constriction). At baseline, PC-1 knockout mice manifested decreased cardiac function relative to littermate controls, and alpha 1C L-type calcium channel protein levels were significantly lower in PC-1 knockout hearts. Whereas control mice manifested robust transverse aortic constriction-induced increases in cardiac mass, PC-1 knockout mice showed no significant growth. Likewise, transverse aortic constriction-elicited increases in hypertrophic markers and interstitial fibrosis were blunted in the knockout animals Conclusion-PC-1 is a cardiomyocyte mechanosensor that is required for cardiac hypertrophy through a mechanism that involves stabilization of alpha 1C protein.en_US
Patrocinadordc.description.sponsorshipFondo Nacional de Desarrollo Cientifico y Tecnologico, FONDECYT 3110039 1150887 11130267en_US
Lenguagedc.language.isoenen_US
Publisherdc.publisherLippicott Williams & Wilkinsen_US
Type of licensedc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile*
Link to Licensedc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
Keywordsdc.subjectCardiomegalyen_US
Keywordsdc.subjectMechanotransduction, cellularen_US
Títulodc.titlePolycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stabilityen_US
Document typedc.typeArtículo de revistaen_US


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Atribución-NoComercial-SinDerivadas 3.0 Chile
Except where otherwise noted, this item's license is described as Atribución-NoComercial-SinDerivadas 3.0 Chile