Abstract
Accumulating evidences have demonstrated that RhoA/Rho-kinase pathway plays a pivotal role in various cellular functions. The aim of this study was to explore whether RhoA/Rho-kinase pathway is involved in the pathogenesis of high flow induced pulmonary hypertension and whether long-term inhibition of RhoA/Rho-kinase pathway with fasudil could attenuate high flow induced pulmonary artery remodeling in rats. Wistar rats in the shunt groups and treated groups were underwent left common carotid artery–external jugular vein shunt operation, rats in control groups were sham-operated animals. Rats in treated groups received fasudil treatment, the others received same dose of saline. At week 4, 8 of the study, rats were underwent haemodynamics measurements, pulmonary artery morphologic assessments, detection of pulmonary artery smooth muscle cells (SMCs) proliferation and apoptosis. RhoA and Rho-kinase activity in pulmonary arteries were also analyzed. Compared with the control groups, exposure to high blood flow induced a significant elevation of right ventricle systolic pressure at week 8, significant increase of the mean percentage of media wall thickness (%MT) in moderate size pulmonary arteries both at weeks 4 and 8, marked elevation of right ventricle (RV) to left ventricle plus septum (LV + SP) weight ratio at week 8, significant increase of PCNA-positive SMCs percentage at week 4 and significant decrease of TUNEL-positive SMCs percentage both at weeks 4 and 8. High pulmonary blood flow also induced 3.19 ± 0.28-fold increase of RhoA and 3.63 ± 0.52-fold increase of Rho-kinase over the control group at week 4, 1.57 ± 0.35-fold increase of RhoA and 2.36 ± 0.39-fold increase of Rho-kinase over the control group at week 8. Compared with the shunt groups, fasudil treatment significantly suppressed Rho-kinase activity at both weeks 4 and 8, improved pulmonary hypertension at week 8, attenuated right ventricular hypertrophy at week 8, and enhanced pulmonary vascular remodeling both at weeks 4 and 8, which were associated with suppressed pulmonary artery smooth muscle cells proliferation at week 4 and apoptosis both at weeks 4 and 8. These results indicated that RhoA/Rho-kinase mediated pathway participated in the process of high flow induced pulmonary artery remodeling; inhibition of Rho kinase with fasudil could attenuate pulmonary artery remodeling.
Published Version
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