title: Targeted genomic disruption of h-ras induces hypotension through a NO-cGMP-PKG pathway-dependent mechanism.
abstract: 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 methods: direct 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.
authors.affiliation: Department of Physiology, Universidad de Alcala, Alcala de Henares, Spain. aranzazu.chamorro@nyumc.org
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Chamorro-Jorganes
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Grande
authors.forename: Beatriz
authors.initials: B
authors.lastname: Herranz
authors.forename: Mirjana
authors.initials: M
authors.lastname: Jerkic
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera
authors.forename: Maria
authors.initials: M
authors.lastname: Gonzalez-Nuñez
authors.forename: Eugenio
authors.initials: E
authors.lastname: Santos
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez-Puyol
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Lopez-Novoa
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Puyol
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D007022:Hypotension / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D018709:Statistics, Nonparametric; D015854:Up-Regulation / Q000502:physiology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D017869:Cyclic GMP-Dependent Protein Kinases; D018631:ras Proteins; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP