title: Rho-kinase inhibition alleviates pulmonary hypertension in transgenic mice expressing a dominant-negative type II bone morphogenetic protein receptor gene.
abstract: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a sustained elevation in the pulmonary artery pressure and subsequent right heart failure. The activation of Rho/Rho-kinase activity and the beneficial effect of Rho-kinase inhibition have been demonstrated in several experimental models of pulmonary hypertension. However, it remains unclear whether Rho-kinase inhibitors can also be used against pulmonary hypertension associated with mutations in the type II bone morphogenetic protein receptor (BMPRII) gene. Transgenic mice expressing a dominant-negative BMPRII gene (with an arginine to termination mutation at amino acid 899) in smooth muscle by a tetracycline-gene switch system (SM22-tet-BMPR2(R899X) mice) were examined. They developed an elevated right ventricular systolic pressure (RVSP), right ventricular (RV) hypertrophy, muscularization of small pulmonary arteries, and an associated disturbed blood flow in their lungs. The Rho/Rho-kinase activity and Smad activity were determined by a Western blot analysis by detecting GTP-RhoA and the phosphorylation of myosin phosphatase target subunit 1, Smad1, and Smad2. In the lungs of SM22-tet-BMPR2(R899X) mice, the Rho/Rho-kinase activity was elevated significantly, whereas the Smad activity was almost unchanged. Fasudil, a Rho-kinase inhibitor, significantly decreased RVSP, alleviated RV hypertrophy and muscularization of small pulmonary arteries, and improved blood flow in SM22-tet-BMPR2(R899X) mice, although it did not alter Smad signaling. Our study demonstrates that Rho/Rho-kinase signaling is activated via a Smad-independent pathway in an animal model of pulmonary hypertension with a BMPRII mutation in the cytoplasmic tail domain. Rho-kinase inhibition is therefore a possible therapeutic approach for the treatment of PAH associated with genetic mutation.
authors.affiliation: Dept. of Respirology (B2 Graduate School of Medicine, Chiba Univ., 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. ytada25@yahoo.co.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yasuda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.forename: James
authors.initials: J
authors.lastname: West
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D047428:Protein Kinase Inhibitors; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C010781:acute-phase protein rho; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; C049347:fasudil