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dc.contributor.authorRivera-Torres, Jose 
dc.contributor.authorGuzman-Martinez, Gabriela 
dc.contributor.authorVilla-Bellosta, Ricardo 
dc.contributor.authorOrbe, Josune
dc.contributor.authorGonzalez-Gomez, Cristina 
dc.contributor.authorSerrano, Manuel
dc.contributor.authorDíez, Javier
dc.contributor.authorAndres, Vicente 
dc.contributor.authorMaraver, Antonio
dc.identifier.citationFisiopatología Cardiovascular Molecular y Genéticaes_ES
dc.description.abstractOBJECTIVE: The Notch pathway has been linked to pulmonary hypertension, but its role in systemic hypertension and, in particular in left ventricular hypertrophy (LVH), remains poorly understood. The main objective of this work was to analyse the effect of inhibiting the Notch pathway on the establishment and maintenance of angiotensin II (Ang-II)-induced arterial hypertension and LVH in adult mice with inducible genetic deletion of γ-secretase, and to test preclinically the therapeutic efficacy of γ-secretase inhibitors (GSIs). BASIC METHODS: We analysed Ang-II responses in primary cultures of vascular smooth muscle cells obtained from a novel mouse model with inducible genetic deletion of the γ-secretase complex, and the effects of GSI treatment on a mouse cardiac cell line. We also investigated Ang-II-induced hypertension and LVH in our novel mouse strain lacking the γ-secretase complex and in GSI-treated wild-type mice. Moreover, we analysed vascular tissue from hypertensive patients with and without LVH. MAIN RESULTS: Vascular smooth muscle cells activate the Notch pathway in response to Ang-II both 'in vitro' and 'in vivo'. Genetic deletion of γ-secretase in adult mice prevented Ang-II-induced hypertension and LVH without causing major adverse effects. Treatment with GSI reduced Ang-II-induced hypertrophy of a cardiac cell line 'in vitro' and LVH in wild-type mice challenged with Ang-II. We also report elevated expression of the Notch target HES5 in vascular tissue from hypertensive patients with LVH compared with those without LVH. CONCLUSION: The Notch pathway is activated in the vasculature of mice with hypertension and LVH, and its inhibition via inducible genetic γ-secretase deletion protects against both conditions. Preliminary observations in hypertensive patients with LVH support the translational potential of these findings. Moreover, GSI treatment protects wild-type mice from Ang-II-induced LVH without affecting blood pressure. Our results unveil the potential use of GSIs in the treatment of hypertensive patients with LVH.es_ES
dc.description.sponsorshipJuan de la Cierva postdoctoral contract from MINECO [JCI-2011-09663]; MINECO; ProCNIC Foundation; Spanish Ministry of Economy and Competitivity (MINECO) [SAF2013-46663-R]; Instituto de Salud Carlos III [RD12/0042/0028, RD12/0042/0009, MS-00151]; Inserm (jeune chercheur accueilli)es_ES
dc.publisherLippincott, Williams & Wilkinses_ES
dc.subject.meshAmyloid Precursor Protein Secretases es_ES
dc.subject.meshAngiotensin II es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshBlood Pressure es_ES
dc.subject.meshCardiomegaly es_ES
dc.subject.meshCells, Cultured es_ES
dc.subject.meshDibenzazepines es_ES
dc.subject.meshDisease Models, Animales_ES
dc.subject.meshDrug Evaluation, Preclinical es_ES
dc.subject.meshHumans es_ES
dc.subject.meshHypertension es_ES
dc.subject.meshHypertrophy, Left Ventricular es_ES
dc.subject.meshMale es_ES
dc.subject.meshMice es_ES
dc.subject.meshMiddle Aged es_ES
dc.subject.meshMuscle, Smooth, Vasculares_ES
dc.subject.meshSignal Transduction es_ES
dc.titleTargeting γ-secretases protect against angiotensin II-induced cardiac hypertrophyes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.identifier.journalJournal of hypertensiones_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genéticaes_ES

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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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