| First Author | Martín-Sánchez P | Year | 2018 |
| Journal | FASEB J | Volume | 32 |
| Issue | 2 | Pages | 920-934 |
| PubMed ID | 29054855 | Mgi Jnum | J:270549 |
| Mgi Id | MGI:6277423 | Doi | 10.1096/fj.201700134RRRR |
| Citation | Martin-Sanchez P, et al. (2018) H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Ibeta pathway activation. FASEB J 32(2):920-934 |
| abstractText | 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-Ibeta 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-3beta-dependent activation of the transcription factor, cAMP response element-binding protein, which is responsible for PKG-Ibeta 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-Ibeta overexpression could play a partial role, and points to H-Ras and/or downstream proteins as potential therapeutic targets in cardiovascular disease.-Martin-Sanchez, P., Luengo, A., Griera, M., Orea, M. J., Lopez-Olaneta, M., Chiloeches, A., Lara-Pezzi, E., de Frutos, S., Rodriguez-Puyol, M., Calleros, L., Rodriguez-Puyol, D. H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Ibeta pathway activation. |
