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Eur J Pediatr Surg 2012; 22(02): 148-156
DOI: 10.1055/s-0032-1308700
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Compensatory Lung Growth in NOS3 Knockout Mice Suggests Synthase Isoform Redundancy

Stefan Pokall
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
2   Department of Cardiovascular Surgery, German Heart Center Munich, Technical University Munich, Munich, Bavaria, Germany
,
Arturo R. Maldonado
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
3   Division of Biomedical Informatics, Center for Computational Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Charles A. Klanke
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Shuichi Katayama
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Lee M. Morris
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Jose F. Vuletin
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Foong-Yen Lim
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
,
Timothy M. Crombleholme
1   Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
› Author Affiliations
Further Information

Publication History

10 October 2011

07 November 2011

Publication Date:
19 April 2012 (online)

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Abstract

Nitric oxide synthase 3 (NOS3) produces nitric oxide (NO) in endothelial cells, which stimulates cyclic guanosine monophosphate (cGMP) production and thereby mediates pulmonary vasodilation. Inhibition of cGMP enzymatic cleavage by sildenafil might be involved in lung growth stimulating processes in pulmonary hypoplasia. The aim of this study was to discover insights into the transcriptional regulation of NOS3 in a mouse model of compensatory lung growth (CLG). CLG was studied in wild type animals (WT) and NOS3 knockout mice (NOS3−/−) by dry weight, DNA, and protein quantification as well as relative quantification of NOS mRNA. All assessments were done on adult female mice, 10 days after left pneumonectomy (PNX) or sham thoracotomy. Weight ratios of right NOS3−/− lungs were no different than controls. There was a compensatory increase in DNA and a noncompensating increase in protein ratios in NOS3−/− mice compared with controls. Pharmacological knockdown with the pan-NOS inhibitor l-NAME (nitro-arginine methyl ester) reduced CLG by only 8% compared with the d-NAME treated control mice. Relative quantification of lung mRNA revealed no up-regulation of NOS3 expression in WT lungs after PNX, but NOS3−/− lungs showed a 2.6-fold higher inducible NOS2 expression compared with shams. These data suggest that NOS3 loss of function alone does not impair CLG in mice, possibly because of redundancy mechanisms involving NOS2.

Keywords

compensatory lung growth - nitric oxide synthase - lung growth - nitric oxide
 

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