Link: http://www.ncbi.nlm.nih.gov/pubmed/25783350

J Pediatr Surg. 2015 Mar 7. pii: S0022-3468(15)00165-7. doi: 10.1016/j.jpedsurg.2015.02.063. [Epub ahead of print]

Increased pulmonary RhoA expression in the nitrofen-induced congenital diaphragmatic hernia rat model.

Takayasu H1, Masumoto K2, Hagiwara K2, Sasaki T2, Ono K2, Jimbo T2, Uesugi T2, Gotoh C2, Urita Y2, Shinkai T2, Tanaka H2.
Author information
1Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: hajimeta@md.tsukuba.ac.jp.
2Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.

Abstract
PURPOSE:
Persistent pulmonary hypertension remains a major cause of mortality and morbidity in cases of congenital diaphragmatic hernia (CDH). Recently, RhoA/Rho-kinase-mediated vasoconstriction has been reported to be important in the pathogenesis of pulmonary hypertension (PH). Several recent reports have described that fasudil, a potent Rho-kinase inhibitor and vasodilator, could represent a potential therapeutic option for PH. We designed this study to investigate the hypothesis that the expression level of RhoA is increased in the nitrofen-induced CDH rat model. The expression level of Wnt11, an activator of RhoA, was also evaluated.

METHODS:
Pregnant rats were treated with or without nitrofen on gestational day 9 (D9). Fetuses were sacrificed on D17, D19 and D21 and were divided into control and CDH groups. Quantitative real-time polymerase chain reaction was performed to determine the pulmonary gene expression levels of both Wnt11 and RhoA. An immunofluorescence study was also performed to evaluate the expression and localization of RhoA.

RESULTS:
The relative mRNA expression levels of pulmonary Wnt11 and RhoA on D21 were significantly increased in the CDH group compared with the control group (p=0.016 and p=0.008, respectively). The immunofluorescence study confirmed the overexpression of RhoA in the pulmonary vessels of CDH rats on D21.

CONCLUSIONS:
Our results provide evidence that the RhoA/Rho-kinase-mediated pathway is involved in the pathogenesis of PH in the nitrofen-induced CDH rat model. Our data also suggest that the fasudil, a Rho-kinase inhibitor, could represent a therapeutic option for the treatment of PH in CDH.

Copyright © 2015. Published by Elsevier Inc.

KEYWORDS:
Congenital diaphragmatic hernia; Nitrofen; Pulmonary hypertension; RhoA/Rho-kinase; Vasoconstrictor
PMID: 25783350 [PubMed - as supplied by publisher]