H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Ibeta pathway activation
Authors
Martín Sánchez, Paloma; Luengo Rodríguez, Alicia; Griera Merino, Mercedes; Orea Martínez, María Jesús; López Oleñata, María; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/58818DOI: 10.1096/fj.201700134RRRR
ISSN: 0892-6638
Date
2018-02Affiliation
Universidad de Alcalá. Departamento de Bioquímica y Biología Molecular; Universidad de Alcalá. Departamento de Medicina y Especialidades Médicas; Universidad de Alcalá. Departamento de Biología de SistemasFunders
Instituto de Salud Carlos III
Universidad de Alcalá
Fundación Senefro
FEDER
Bibliographic citation
Martín-Sánchez P, Luengo A, Griera M, et al. H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation. FASEB J. 2018;32(2):920-934. doi:10.1096/fj.201700134RRRR
Keywords
PKG
CREB
H-ras2/2
Cardiac hypertrophy
Description / Notes
15 p.
Project
info:eu-repo/grantAgreement/ISCIII//PI11%2F01630/ES//
info:eu-repo/grantAgreement/ISCIII//PI14%2F01939/ES//
info:eu-repo/grantAgreement/ISCIII//PI14%2F02075/ES//
info:eu-repo/grantAgreement/ISCIII/REDinREN/RD12%2F0021%2F0006/ES//
info:eu-repo/grantAgreement/ISCIII/REDinREN/RD16%2F0009%2F0018/ES//
info:eu-repo/grantAgreement/UAH//CCG2015%2FBIO-034/ES//
info:eu-repo/grantAgreement/UAH//CCG2016%2FBIO-043/ES//
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/publishedVersion
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs.We have demonstrated that H-rasgene deletion produces mice hypotensionviaa soluble guanylate cyclase-proteinkinase G (PKG)–dependent mechanism. In this study, we analyzed the consequences of H-rasdeletiononcardiacremodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Leftventricular posterior wall thickness and mass and cardiomyocyte cross-sectional area were similar between AngII-treated H-Ras knockout (H-ras2/2) and control wild-type (H-ras+/+) mice, as were extracellular matrix proteinexpression. Increased cardiac PKG-Ibprotein expression in H-ras2/2mice suggests the involvement of this proteinin heart protection.Ex vivoexperiments on cardiac explants could support this mechanism, as PKG blockadeblunted protection against AngII-induced cardiac hypertrophy and fibrosis markers in H-ras2/2mice. Geneticmodulation studies in cardiomyocytes and cardiac and embryonic fibroblasts revealed that the lack of H-Ras down-regulates the B-RAF/MEK/ERK pathway, which induces the glycogen synthase kinase-3b-dependent activation ofthe transcription factor, cAMP response element-binding protein, which is responsible for PKG-Iboverexpressionin H-ras2/2mouse embryonic fibroblasts. This study demonstrates that H-rasdeletion protects against AngII-induced cardiac remodeling, possiblyviaa mechanism in which PKG-Iboverexpression could play a partial role, andpoints to H-Ras and/or downstream proteins as potential therapeutic targets in cardiovascular disease.
Files in this item
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H-ras_martin_FASEBJ_2018.pdf | 2.277Mb |
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H-ras_martin_FASEBJ_2018.pdf | 2.277Mb |
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