Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs
Author
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López, Nandy
Author
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Ebensperger Darrouy, Germán
Author
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Herrera Videla, Emilio
Author
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Reyes, Roberto V.
Author
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Calaf, Gloria
Author
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Cabello, Gertrudis
Author
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Moraga, Fernando
Author
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Benaldo, Felipe A.
Author
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Díaz, Marcela
Author
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Parer, Julian T.
Author
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Llanos Mansilla, Jorge
Admission date
dc.date.accessioned
2016-11-23T18:21:42Z
Available date
dc.date.available
2016-11-23T18:21:42Z
Publication date
dc.date.issued
2016
Cita de ítem
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Am J Physiol Regul Integr Comp Physiol 310: R1053–R1063, 2016
es_ES
Identifier
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10.1152/ajpregu.00177.2015
Identifier
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https://repositorio.uchile.cl/handle/2250/141386
Abstract
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Exposure to high-altitude chronic hypoxia during pregnancy may cause pulmonary hypertension in neonates, as a result of vasoconstriction and vascular remodeling. We hypothesized that susceptibility to pulmonary hypertension, due to an augmented expression and activity of the RhoA/Rho-kinase (ROCK) pathway in these neonates, can be reduced by daily administration of fasudil, a ROCK inhibitor. We studied 10 highland newborn lambs with conception, gestation, and birth at 3,600 m in Putre, Chile. Five highland controls (HLC) were compared with 5 highland lambs treated with fasudil (HL-FAS; 3 mg.kg (1).day (1) iv for 10 days). Ten lowland controls were studied in Lluta (50 m; LLC). During the 10 days of fasudil daily administration, the drug decreased pulmonary arterial pressure (PAP) and resistance (PVR), basally and during a superimposed episode of acute hypoxia. HL-FAS small pulmonary arteries showed diminished muscular area and a reduced contractile response to the thromboxane analog U46619 compared with HLC. Hypoxia, but not fasudil, changed the protein expression pattern of the RhoA/ROCKII pathway. Moreover, HL-FAS lungs expressed less pMYPT1(T850) and pMYPT1T(696) than HLC, with a potential increase of the myosin light chain phosphatase activity. Finally, hypoxia induced RhoA, ROCKII, and PKG mRNA expression in PASMCs of HLC, but fasudil reduced them (HL-FAS) similarly to LLC. We conclude that fasudil decreases the function of the RhoA/ROCK pathway, reducing the PAP and PVR in chronically hypoxic highland neonatal lambs. The inhibition of ROCKs by fasudil may offer a possible therapeutic tool for the pulmonary hypertension of the neonates.
es_ES
Patrocinador
dc.description.sponsorship
Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT-Chile)
3100080
1120605
1130424
1151119
1140647