Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase

• Published in: American journal of physiology. Lung cellular and molecular physiology 2004-10, Vol.287 (4), p.L656-L664
• Main Authors: Fagan, Karen A, Oka, Masahiko, Bauer, Natalie R, Gebb, Sarah A, Ivy, D. Dunbar, Morris, Kenneth G, McMurtry, Ivan F
• Format: Article
• Language: English
• Subjects: Amides - therapeutic use; Animals; Cardiomegaly - physiopathology; Enzyme Inhibitors - therapeutic use; Hematocrit; Hypertension, Pulmonary - prevention & control; Hypoxia; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Lung - drug effects; Lung - physiology; Male; Mice; Mice, Inbred C57BL; Perfusion; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pulmonary Circulation - drug effects; Pulmonary Circulation - physiology; Pyridines - therapeutic use; rho-Associated Kinases; Vasoconstriction - drug effects; Ventricular Dysfunction, Right - pathology; Ventricular Dysfunction, Right - physiopathology; Ventricular Function, Right - drug effects; Ventricular Function, Right - physiology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00090.2003

1 Cardiovascular Pulmonary Research Laboratory and 2 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262 Submitted 1 April 2003 ; accepted in final form 13 February 2004 RhoA GTPase mediates a variety of cellular responses, including activation of the contractile apparatus, growth, and gene expression. Acute hypoxia activates RhoA and, in turn, its downstream effector, Rho-kinase, and previous studies in rats have suggested a role for Rho/Rho-kinase signaling in both acute and chronically hypoxic pulmonary vasoconstriction. We therefore hypothesized that activation of Rho/Rho-kinase in the pulmonary circulation of mice contributes to acute hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension and vascular remodeling. In isolated, salt solution-perfused mouse lungs, acute administration of the Rho-kinase inhibitor Y-27632 (1 x 10 –5 M) attenuated hypoxic vasoconstriction as well as that due to angiotensin II and KCl. Chronic treatment with Y-27632 (30 mg·kg –1 ·day –1 ) via subcutaneous osmotic pump decreased right ventricular systolic pressure, right ventricular hypertrophy, and neomuscularization of the distal pulmonary vasculature in mice exposed to hypobaric hypoxia for 14 days. Analysis of a small number of proximal pulmonary arteries suggested that Y-27632 treatment reduced the level of phospho-CPI-17, a Rho-kinase target, in hypoxic lungs. We also found that endothelial nitric oxide synthase protein in hypoxic lungs was augmented by Y-27632, suggesting that enhanced nitric oxide production might have played a role in the Y-27632-induced attenuation of chronically hypoxic pulmonary hypertension. In conclusion, Rho/Rho-kinase activation is important in the effects of both acute and chronic hypoxia on the pulmonary circulation of mice, possibly by contributing to both vasoconstriction and vascular remodeling. RhoA; Y-27632 Address for reprint requests and other correspondence: K. A. Fagan, Cardiovascular Pulmonary Research Laboratory, Univ. of Colorado Health Sciences Center, 4200 E. Ninth Ave., B-133, Denver, CO 80262 (E-mail: karen.fagan{at}uchsc.edu )