Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats.
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.
Li
Fuhai
F
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University Qilu Hospital, Jinan, China.
Xia
Wei
W
Li
Aiwu
A
Zhao
Cuifen
C
Sun
Ruopeng
R
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000187:drug effects; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C049347:fasudil