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dc.contributor.authorVilla-Bellosta, Ricardo 
dc.contributor.authorRivera-Torres, Jose 
dc.contributor.authorOsorio, Fernando G
dc.contributor.authorAcin-Perez, Rebeca 
dc.contributor.authorEnriquez, José Antonio 
dc.contributor.authorLópez-Otín, Carlos
dc.contributor.authorAndres, Vicente
dc.identifier.citationCirculation. 2013; 127(24):2442-51es_ES
dc.description.abstractBACKGROUND: Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to premature death, predominantly of myocardial infarction or stroke. The goal of this study was to investigate mechanisms that cause excessive vascular calcification in HGPS. METHODS AND RESULTS: We performed expression and functional studies in wild-type mice and knock-in Lmna(G609G/+) mice expressing progerin, which mimic the main clinical manifestations of HGPS. Lmna(G609G/+) mice showed excessive aortic calcification, and primary aortic vascular smooth muscle cells from these progeroid animals had an impaired capacity to inhibit vascular calcification. This defect in progerin-expressing vascular smooth muscle cells is associated with increased expression and activity of tissue-nonspecific alkaline phosphatase and mitochondrial dysfunction, which leads to reduced ATP synthesis. Accordingly, Lmna(G609G/+) vascular smooth muscle cells are defective for the production and extracellular accumulation of pyrophosphate, a major inhibitor of vascular calcification. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of Lmna(G609G/+) mice without changes in phosphorus and calcium. Treatment with pyrophosphate inhibited vascular calcification in progeroid mice. CONCLUSIONS: Excessive vascular calcification in Lmna(G609G) mice is caused by reduced extracellular accumulation of pyrophosphate that results from increased tissue-nonspecific alkaline phosphatase activity and diminished ATP availability caused by mitochondrial dysfunction in vascular smooth muscle cells. Excessive calcification is ameliorated on pyrophosphate treatment. These findings reveal a previously undefined pathogenic process in HGPS that may also contribute to vascular calcification in normal aging, because progerin progressively accumulates in the vascular tissue of individuals without HGPS.es_ES
dc.description.sponsorshipWork in the authors’ laboratory is supported by grants from the Ministerio de Economía y Competitividad (MINECO; SAF201016044), Instituto de Salud Carlos III (RD06/0014/0021 and RD12/0042/0028), and the Progeria Research Foundation. Dr VillaBellosta holds a Juan de la Cierva postdoctoral contract from MINECO (JCI-2011–09663). Dr López-Otín is an investigator of the Botín Foundation. The Instituto Universitario de Oncología is supported by Obra Social Cajastur and the Centro Nacional de Investigaciones Cardiovasculares by MINECO and Fundación Pro-CNIC.es_ES
dc.subjectHutchinson-Gilford progeria syndromees_ES
dc.subjectmuscle, smoothes_ES
dc.subjecttissue-non specific alkaline phosphatasees_ES
dc.subjectvascular calcificationes_ES
dc.subject.meshAdenosine Triphosphate es_ES
dc.subject.meshAlkaline Phosphatase es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshAorta es_ES
dc.subject.meshCells, Cultured es_ES
dc.subject.meshDiphosphates es_ES
dc.subject.meshDisease Models, Animales_ES
dc.subject.meshLamin Type A es_ES
dc.subject.meshMale es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Inbred C57BL es_ES
dc.subject.meshMice, Mutant Strains es_ES
dc.subject.meshMitochondria, Muscle es_ES
dc.subject.meshMuscle, Smooth, Vasculares_ES
dc.subject.meshProgeria es_ES
dc.subject.meshTreatment Outcome es_ES
dc.subject.meshVascular Calcification es_ES
dc.titleDefective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of Hutchinson-Gilford progeria syndrome that is ameliorated on pyrophosphate treatmentes_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderProgeria Research Foundationes_ES
dc.contributor.funderFundación Botínes_ES
dc.contributor.funderFundación Cajastures_ES
dc.contributor.funderFundación ProCNICes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genéticaes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Genética Funcional del Sistema de Fosforilación Oxidativaes_ES

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
This item is licensed under a: Attribution-NonCommercial-NoDerivatives 4.0 Internacional