title: Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs.
abstract: 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.
authors.affiliation: Laboratorio de Fisiología y Fisiopatología del Desarrollo, Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile;
authors.forename: Nandy C
authors.initials: NC
authors.lastname: Lopez
authors.affiliation: Laboratorio de Fisiología y Fisiopatología del Desarrollo, Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile;
authors.forename: German
authors.initials: G
authors.lastname: Ebensperger
authors.affiliation: Laboratorio de Fisiología y Fisiopatología del Desarrollo, Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile;
authors.forename: Emilio A
authors.initials: EA
authors.lastname: Herrera
authors.affiliation: Laboratorio de Fisiología y Fisiopatología del Desarrollo, Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile;
authors.forename: Roberto V
authors.initials: RV
authors.lastname: Reyes
authors.affiliation: Instituto de Alta Investigación, Universidad de Tarapacá, Arica, Chile;
authors.forename: Gloria
authors.initials: G
authors.lastname: Calaf
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Tarapacá, Arica, Chile;
authors.forename: Gertrudis
authors.initials: G
authors.lastname: Cabello
authors.affiliation: Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile;
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Moraga
authors.affiliation: Laboratorio de Fisiología y Fisiopatología del Desarrollo, Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile;
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Beñaldo
authors.affiliation: Laboratorio de Fisiología y Fisiopatología del Desarrollo, Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Departamento de Promoción de la Salud de la Mujer y el Recién Nacido, Facultad de Medicina, Universidad de Chile, Santiago, Chile; and.
authors.forename: Marcela
authors.initials: M
authors.lastname: Diaz
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California.
authors.forename: Julian T
authors.initials: JT
authors.lastname: Parer
authors.affiliation: Laboratorio de Fisiología y Fisiopatología del Desarrollo, Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Santiago, Chile; allanos@med.uchile.cl.
authors.forename: Anibal J
authors.initials: AJ
authors.lastname: Llanos
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000532:Altitude Sickness / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000378:metabolism / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C049347:fasudil
keywords: Rho kinase; high altitude; hypoxia; newborn; pulmonary hypertension