Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat

• Published in: Journal of applied physiology (1985) 2006-03, Vol.100 (3), p.996-1002
• Main Authors: Nagaoka, Tetsutaro, Gebb, Sarah A, Karoor, Vijaya, Homma, Noriyuki, Morris, Kenneth G, McMurtry, Ivan F, Oka, Masahiko
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Altitude; Animals; Biological and medical sciences; Blood Pressure - physiology; Blotting, Western; Calcium - pharmacology; Calcium - physiology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Hemodynamics - drug effects; Hypertension; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - metabolism; Hypertrophy, Right Ventricular - metabolism; Intracellular Signaling Peptides and Proteins; Protein-Serine-Threonine Kinases - analysis; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pulmonary Alveoli - pathology; Pulmonary arteries; Pulmonary Artery - chemistry; Pulmonary Artery - pathology; Rats; Rats, Inbred Strains; rho-Associated Kinases; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Rodents; Signal Transduction; Vasoconstriction - drug effects
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.01028.2005

Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado Submitted 23 August 2005 ; accepted in final form 29 November 2005 The fawn-hooded rat (FHR) develops severe pulmonary hypertension (PH) when raised for the first 3–4 wk of life in the mild hypoxia of Denver’s altitude (5,280 ft.). The PH is associated with sustained pulmonary vasoconstriction and pulmonary artery remodeling. Furthermore, lung alveolarization and vascularization are reduced in the Denver FHR. We have recently shown that RhoA/Rho kinase signaling is involved in both vasoconstriction and vascular remodeling in animal models of hypoxic PH. In this study, we investigated the role of RhoA/Rho kinase signaling in the PH of Denver FHR. In -toxin permeabilized pulmonary arteries from Denver FHR, the contractile sensitivity to Ca 2+ was increased compared with those from sea-level FHR. RhoA activity and Rho kinase I protein expression in pulmonary arteries of Denver FHR (10-wk-old) were higher than in those of sea-level FHR. Acute inhalation of the Rho kinase inhibitor fasudil selectively reduced the elevated pulmonary arterial pressure in Denver FHR in vivo. Chronic fasudil treatment (30 mg·kg –1 ·day –1 , from birth to 10 wk old) markedly reduced the development of PH and improved lung alveolarization and vascularization in Denver FHR. These results suggest that Rho kinase-mediated sustained vasoconstriction, through increased Ca 2+ sensitivity, plays an important role in the established PH and that RhoA/Rho kinase signaling contributes significantly to the development of PH and lung dysplasia in mild hypoxia-exposed FHR. Ca 2+ sensitivity; fasudil; vascular remodeling; lung dysplasia Address for reprint requests and other correspondence: M. Oka, CVP Research Laboratory, B-133, UCDHSC, 4200 East Ninth Ave., Denver, CO 80262 (e-mail: masahiko.oka{at}uchsc.edu )