Role of the rhoa/rock pathway in high-altitude associated neonatal pulmonary hypertension in lambs
| Autor: | Gloria M. Calaf, Gertrudis Cabello, Roberto V. Reyes, Emilio A. Herrera, Germán Ebensperger, Marcela Díaz, Fernando A. Moraga, Felipe A. Beñaldo, Nandy López, Julian T. Parer, Aníbal J. Llanos |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty RHOA Physiology Thromboxane Hypertension Pulmonary 030204 cardiovascular system & hematology Altitude Sickness Infant Newborn Diseases 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine medicine Animals Humans Rho-associated protein kinase Protein Kinase Inhibitors Altitude sickness rho-Associated Kinases Sheep biology business.industry Fasudil Infant Newborn Hypoxia (medical) medicine.disease Pulmonary hypertension 030104 developmental biology Endocrinology Treatment Outcome Animals Newborn Anesthesia biology.protein medicine.symptom business rhoA GTP-Binding Protein Vasoconstriction Signal Transduction |
| Zdroj: | American Journal Of Physiology-Regulatory Integrative And Comparative Physiology Artículos CONICYT CONICYT Chile instacron:CONICYT |
| Popis: | 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 pMYPT1T850 and pMYPT1T696 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. |
| Databáze: | OpenAIRE |
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