Inhibition of rho kinase attenuates high flow induced pulmonary hypertension in rats

• Published in: Chinese medical journal Vol. 120; no. 1; pp. 22 - 29
• Main Authors: Li, Fu-Hai, Xia, Wei, Li, Ai-Wu, Zhao, Cui-Fen, Sun, Ruo-Peng
• Format: Journal Article
• Language: English
• Published: China The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University Qilu Hospital, Jinan 250012,China 05.01.2007
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use; Animals; Cell Proliferation - drug effects; Enzyme Activation - drug effects; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - etiology; Hypertrophy, Right Ventricular - prevention & control; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - physiology; Male; Muscle, Smooth, Vascular - drug effects; Protein Kinase Inhibitors - therapeutic use; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - physiology; Pulmonary Artery - pathology; Pulmonary Circulation - drug effects; Rats; Rats, Wistar; rho-Associated Kinases; rhoA GTP-Binding Protein - physiology; Systole - drug effects; Vasoconstriction - drug effects; 肺动脉高血压; 肺循环; 肺部疾病; hypertension,pulmonary; heart defects,congenital; fasudil; rho-associated kinase
• ISSN: 0366-6999; 2542-5641
• DOI: 10.1097/00029330-200701010-00005

Background The RhoA/Rho kinase pathway may participate in the pathogenesis of hypoxia and monocrotaline induced pulmonary hypertension. This study tested whether RhoA/Rho kinase pathway is involved in the pathogenesis of high flow induced pulmonary hypertension in rats. Methods Male Wistar rats （4 weeks） were randomly divided into 4 shunt groups, 4 treated groups and 4 control groups. Shunt and treated groups underwent left common carotid artery/external jugular vein shunt operation. Control groups underwent sham operation. Treated groups received fasudil treatment and the others received same dose of saline. At weeks 1, 2, 4 and 8 of the study, nght ventricular systolic pressure was measured and blood gases were analysed to calculate Qp/Qs. The weight ratio of right ventricle to left ventricle plus septum and the mean percentage of medial wall thickness in moderate sized pulmonary arteries were obtained. RhoA activity in pulmonary arteries was detected using Rho activity assay reagent. Rho kinase activity was quantified by the extent of MYPT1 phosphorylation with Western blot. Proliferating cells were evaluated using proliferating cell nuclear antigen immunohistological staining, Results Carotid artery/jugular vein shunt resulted in high pulmonary blood flow, both an acute and a chronic elevation of right ventricular systolic pressure, significant medial wall thickening characterized by smooth muscle cells proliferation, nght ventricular hypertrophy and increased activation of RhoA and Rho kinase. Fasudil treatment lowered pulmonary artery systolic pressure, suppressed pulmonary artery smooth muscle cells proliferation, attenuated pulmonary artery medial wall thickening and inhibited right ventricular hypertrophy together with significant suppression of Rho kinase activity but not Rho activity. Conclusions Activated RhoNRho kinase pathway is associated with both the acute pulmonary vasoconstriction and the chronic pulmonary artery remodelling of high flow induced pulmonary hypertension. Fasudil treatment could improve pulmonary hypertension by inhibiting Rho kinase activity.