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Rho Guanosine Triphosphatases in Lung Development and Pulmonary Hypertension* FREE TO VIEW

Jonathan Kaufman, MD; Eiko Sakao, MD; Masahiko Oka, MD; Tetsu Nagaoka, MD; Cheryl K. Oliver-Picket, MD; Peter L. Jones, MD; Ivan F. McMurtry, MD; Sarah A. Gebb, MD
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*From the Departments of Medicine and Pediatrics, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Sarah A. Gebb, MD, B-133, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262; e-mail: sarrah.gebb@uchsc.edu

Chest. 2005;128(6_suppl):610S. doi:10.1378/chest.128.6_suppl.610S
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The fawn-hooded rat (FHR) raised from birth at the altitude in Denver acquires severe pulmonary hypertension (PH). However, neonates raised at sea level (3 weeks postnatal) and then transferred to Denver do not acquire PH. This suggests a developmental component in the pathogenesis of PH in this model. We investigated the role of the RhoA/Rho-kinase signaling pathway in postnatal lung development and the development of PH.

Aberrant RhoA/Rho-kinase signaling has been implicated in both systemic and PH. This pathway also plays important roles in a wide variety of cell functions central to embryonic and neonatal development, including proliferation, migration, and differentiation. FHR pups were raised in normoxia (sea level, 0 m) or mild hypoxia (the altitude at Denver, 1,500 m). Fasudil, a Rho-kinase inhibitor, was administered orally (30 mg/kg) from birth to rats raised in Denver. Lung tissue was collected at 1 week, 2 weeks, 3 weeks, and 4 weeks postnatally. RhoA, Rho-kinase, Rac1, and RhoE were measured by Western analysis.

An increase in right ventricular weight and a decrease in lung alveolarization were observed in FHRs raised in Denver. This was accompanied by increased active RhoA and Rho-kinase in the lungs and a decreased activation of Rac1 and RhoE, two Rho guanosine triphosphatases that oppose RhoA signaling. Inhibition of Rho-kinase by fasudil in Denver-raised FHRs improved alveolarization, prevented the development of PH, as measured by mean pulmonary artery pressure, and right ventricular hypertrophy. Fasudil treatment also decreased active RhoA and increased active RhoE and Rac1. Increased RhoA/Rho-kinase signaling during postnatal lung development contributes to aberrant lung alveolarization and the development of PH.

Abbreviations: FHR = fawn-hooded rat; PH = pulmonary hypertension

Supported by American Heart Association Scientist Development grant 0330199N.




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