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

Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H-ras gene deletion producesmice 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-I beta 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-3b-dependent activation of the transcription factor, cAMP response element-binding protein, which is responsible for PKG-I beta 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-I beta overexpression could play a partial role, and points to H-Ras and/ordownstream proteins as potential therapeutic targets in cardiovascular disease.