Targeted Genomic Disruption of H-Ras Induces Hypotension Through a NO-cGMP-PKG Pathway–Dependent Mechanism

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 56; no. 3; pp. 484 - 489
• Main Authors: Chamorro-Jorganes, Aranzazu, Grande, Maria Teresa, Herranz, Beatriz, Jerkic, Mirjana, Griera, Mercedes, Gonzalez-Nuñez, Maria, Santos, Eugenio, Rodriguez-Puyol, Diego, Lopez-Novoa, Jose Miguel, Rodriguez-Puyol, Manuel
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.09.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Aorta - metabolism; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - physiology; Blotting, Northern; Blotting, Western; Cardiology. Vascular system; Cells, Cultured; Coronary heart disease; Cyclic GMP - genetics; Cyclic GMP - metabolism; Cyclic GMP-Dependent Protein Kinases - genetics; Cyclic GMP-Dependent Protein Kinases - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Heart; Hypotension - genetics; Hypotension - metabolism; Immunohistochemistry; Medical sciences; Mice; Mice, Knockout; Nitric Oxide - genetics; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Phosphorylation; ras Proteins - genetics; ras Proteins - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction - physiology; Soluble Guanylyl Cyclase; Statistics, Nonparametric; Up-Regulation - physiology; Hypertension; cGMP-dependent protein kinase; arterial pressure; nitric oxide; H-Ras protein; soluble guanylyl cyclase; cyclic GMP; 3',5'-GMP; Cardiovascular disease
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.110.152587

The aim of the present experiments was to evaluate the differences in arterial pressure between H-Ras lacking mice and control mice and to analyze the mechanisms involved in the genesis of the differences. H-Ras lacking mice and mouse embryonic fibroblasts from these animals were used. Blood pressure was measured using 3 different methodsdirect intraarterial measurement in anesthetized animals, tail-cuff sphygmomanometer, and radiotelemetry. H-Ras lacking mice showed lower blood pressure than control animals. Moreover, the aorta protein content of endothelial nitric oxide synthase, soluble guanylyl cyclase, and cyclic guanosine monophosphate–dependent protein kinase was higher in H-Ras knockout mice than in control animals. The activity of these enzymes was increased, because urinary nitrite excretion, sodium nitroprusside–stimulated vascular cyclic guanosine monophosphate synthesis, and phosphorylated vasoactive-stimulated phosphoprotein in aortic tissue increased in these animals. Furthermore, mouse embryonic fibroblasts from H-Ras lacking mice showed higher cyclic guanosine monophosphate–dependent protein kinase promoter activity than control cells. These results strongly support the upregulation of the nitric oxide-cyclic guanosine monophosphate pathway in H-Ras–deficient mice. Moreover, they suggest that H-Ras pathway could be considered as a therapeutic target for hypertension treatment.