H‐ras deletion protects against angiotensin II–induced arterial hypertension and cardiac remodeling through protein kinase G‐Iβ pathway activation

• Published in: The FASEB journal 2018-02, Vol.32 (2), p.920-934
• Main Authors: Martín‐Sánchez, Paloma, Luengo, Alicia, Griera, Mercedes, Orea, María Jesús, López‐Olañeta, Marina, Chiloeches, Antonio, Lara‐Pezzi, Enrique, Frutos, Sergio, Rodríguez–Puyol, Manuel, Calleros, Laura, Rodríguez–Puyol, Diego
• Format: Article
• Language: English
• Subjects: Angiotensin II - adverse effects; Angiotensin II - pharmacology; Animals; cardiac hypertrophy; Cardiomegaly - chemically induced; Cardiomegaly - enzymology; Cardiomegaly - genetics; Cardiomegaly - prevention & control; CREB; Cyclic GMP-Dependent Protein Kinase Type I - genetics; Cyclic GMP-Dependent Protein Kinase Type I - metabolism; Embryo, Mammalian - enzymology; Embryo, Mammalian - pathology; Enzyme Activation - drug effects; Enzyme Activation - genetics; Fibroblasts - enzymology; Fibroblasts - pathology; Gene Deletion; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Hypertension - chemically induced; Hypertension - enzymology; Hypertension - pathology; H‐ras; MAP Kinase Signaling System; Mice; Mice, Knockout; PKG; Proto-Oncogene Proteins p21(ras) - deficiency
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201700134RRRR

Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H‐ras gene deletion produces mice hypotension via a soluble guanylate cyclase‐protein kinase G (PKG)–dependent mechanism. In this study, we analyzed the consequences of H‐ras deletion on cardiac remodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Left ventricular posterior wall thickness and mass and cardiomyocyte cross‐sectional area were similar between AngII‐treated H‐Ras knockout (H‐ras−/−) and control wild‐type (H‐ras+/+) mice, as were extracellular matrix protein expression. Increased cardiac PKG‐Iβ protein expression in H‐ras−/− mice suggests the involvement of this protein in heart protection. Ex vivo experiments on cardiac explants could support this mechanism, as PKG blockade blunted protection against AngII‐induced cardiac hypertrophy and fibrosis markers in H‐ras−/− mice. Genetic modulation 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‐3β‐dependent activation of the transcription factor, cAMP response element‐binding protein, which is responsible for PKG‐Iβ overexpression in H‐ras−/− mouse embryonic fibroblasts. This study demonstrates that H‐ras deletion protects against AngII‐induced cardiac remodeling, possibly via a mechanism in which PKG‐Iβ overexpression could play a partial role, and points to H‐Ras and/or downstream proteins as potential therapeutic targets in cardiovascular disease.—Martín‐Sánchez, P., Luengo, A., Griera, M., Orea, M. J., López‐Olañeta, M., Chiloeches, A., Lara‐Pezzi, E., de Frutos, S., Rodríguez‐Puyol, M., Calleros, L., Rodriíguez‐Puyol, D. H‐ras deletion protects against angiotensin II–induced arterial hypertension and cardiac remodeling through protein kinase G‐Iβ pathway activation. FASEB J. 32, 920–934 (2018). www.fasebj.org