Targeted Genomic Disruption of H-Ras Induces Hypotension Through a NO-cGMP-PKG Pathway-Dependent Mechanism -- Chamorro-Jorganes et al. 56 (3): 484 -- Hypertension

(Hypertension. 2010;56:484.)
© 2010 American Heart Association, Inc.


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Original Articles


Targeted Genomic Disruption of H-Ras Induces Hypotension Through a NO-cGMP-PKG Pathway–Dependent Mechanism
Aranzazu Chamorro-Jorganes; Maria Teresa Grande; Beatriz Herranz; Mirjana Jerkic; Mercedes Griera; Maria Gonzalez-Nuñez; Eugenio Santos; Diego Rodriguez-Puyol; Jose Miguel Lopez-Novoa; Manuel Rodriguez-Puyol

From the Department of Physiology (A.C.-J., B.H., M.G., D.R.-P., M.R.-P.), Universidad de Alcala, Alcala de Henares, Spain; Instituto "Reina Sofia" de Investigacion Nefrologica (A.C.-J., M.T.G., B.H., M.J., M.G., M.G.-N., D.R.-P., J.M.L.-N., M.R.-P.), Madrid, Spain; Department of Physiology and Pharmacology (M.T.G., M.J., M.G.-N., E.S., J.M.L.-N.), Universidad de Salamanca, Salamanca, Spain; Nephrology Section and Research Unit (D.R.-P.), Hospital Universitario "Principe de Asturias," Alcala de Henares, Spain. Present address for M.J.: Hospital for Sick Children, Toronto, Canada.


Correspondence to Aranzazu Chamorro-Jorganes, Department of Medicine, Leon H. Charney Division of Cardiology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, Smilow 8, 522 First Avenue, New York, NY 10016. E-mail aranzazu.chamorro@nyumc.org


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.


Key Words: arterial pressure • H-Ras protein • nitric oxide • cyclic GMP • soluble guanylyl cyclase • cGMP-dependent protein kinase

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▲ Targeted Genomic Disruption of H-Ras Induces Hypotension Through a NO-cGMP-PKG Pathway–Dependent Mechanism
Targeted Genomic Disruption of H-Ras Induces Hypotension Through a NO-cGMP-PKG Pathway-Dependent Mechanism -- Chamorro-Jorganes et al. 56 (3): 484 -- Hypertension


HIPERTENSIÓN
Investigadores españoles identifican una proteína que podría regular la presión arterial
JANO.es y agencias · 20 Abril 2011 13:16

Han descubierto que ratones manipulados genéticamente para carecer de la proteína H-ras presentan menor presión arterial debido a que aumenta la respuesta celular al óxido nítrico.



Un grupo de investigadores españoles han descubierto que la proteína H-ras podría actuar como modulador de la presión arterial, según los resultados de ensayos en ratones publicados recientemente en Hypertension.

En concreto, han descubierto que ratones carente de dicha proteína por manipulación genética reducían su presión arterial, dado que sin H-ras aumentaba la respuesta celular al óxido nítrico.

“Lo importante es que podemos estar en los albores de la descripción de un nuevo grupo de fármacos antihipertensivos. Podría ocurrir que determinados fármacos capaces de inhibir específicamente H-ras pudieran constituir una nueva clase de fármacos”, asegura el jefe de Nefrología del hospital Universitario Príncipe de Asturias, de Madrid, Diego Rodríguez Puyol.

Tras estos primeros resultados, el siguiente paso es probar los inhibidores de H-ras ya conocidos y modificarlos molecularmente para obtener nuevos tratamientos.

“Desde que se describe una molécula hasta que un fármaco llega al mercado pueden pasar entre 10 y 15 años o más, así que no queremos crear falsas expectativas a nadie, pero lo cierto es que estamos en la línea de salida de un proyecto que puede generar importantes beneficios para todas las personas que padecen hipertensión”, asegura el catedrático de Fisiología de la Universidad de Alcalá, Manuel Rodríguez Puyol.



► Hypertension 2010; 56:484-489
Targeted Genomic Disruption of H-Ras Induces Hypotension Through a NO-cGMP-PKG Pathway-Dependent Mechanism -- Chamorro-Jorganes et al. 56 (3): 484 -- Hypertension

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