Nitric oxide synthases in infants and children with pulmonary hypertension and congenital heart disease

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Abstract

Rationale

Nitric oxide is an important regulator of vascular tone in the pulmonary circulation. Surgical correction of congenital heart disease limits pulmonary hypertension to a brief period.

Objectives

The study has measured expression of endothelial (eNOS), inducible (iNOS), and neuronal nitric oxide synthase (nNOS) in the lungs from biopsies of infants with pulmonary hypertension secondary to cardiac abnormalities (n = 26), compared to a control group who did not have pulmonary or cardiac disease (n = 8).

Methods

eNOS, iNOS and nNOS were identified by immunohistochemistry and quantified in specific cell types.

Measurements and main results

Significant increases of eNOS and iNOS staining were found in pulmonary vascular endothelial cells of patients with congenital heart disease compared to control infants. These changes were confined to endothelial cells and not present in other cell types. Patients who strongly expressed eNOS also had strong expression of iNOS.

Conclusion

Upregulation of eNOS and iNOS occurs at an early stage of pulmonary hypertension, and may be a compensatory mechanism limiting the rise in pulmonary artery pressure.

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Most cited references 31

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Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.

A Giaid, D. Saleh (1995)

Pulmonary hypertension is characterized by abnormal thickening of the pulmonary arteries and increased pulmonary vascular resistance. Nitric oxide is a potent endothelium-derived vasorelaxant substance and an inhibitor of smooth-muscle-cell growth. Nitric oxide is produced in various cell types by the action of an enzyme, nitric oxide synthase. We compared the expression of endothelial nitric oxide synthase in the lungs of control subjects with that in the lungs of patients with pulmonary hypertension. We investigated the expression of endothelial nitric oxide synthase by histochemical and immunohistochemical analysis, in situ hybridization, and Northern blot analysis in the lungs of 22 patients with plexogenic pulmonary arteriopathy (arteriopathy of grades 4 through 6), 24 patients with secondary pulmonary hypertension (arteriopathy of grades 1 through 3), and 23 control subjects. In the lungs of the control subjects, nitric oxide synthase was expressed at a high level in the vascular endothelium of all types of vessels and in the pulmonary epithelium. In contrast, little or no expression of the enzyme was found in the vascular endothelium of pulmonary arteries with severe histologic abnormalities (i.e., plexiform lesions) in patients with pulmonary hypertension. The intensity of the enzyme immunoreactivity correlated inversely with the severity of histologic changes. There was an inverse correlation between the arterial expression of the enzyme and total pulmonary resistance in patients with plexogenic pulmonary arteriopathy (r = -0.766, P = 0.004). Pulmonary hypertension is associated with diminished expression of endothelial nitric oxide synthase. It is possible that decreased expression of nitric oxide synthase may contribute to pulmonary vasoconstriction and to the excessive growth of the tunica media observed in this disease.

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Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease.

Damien Bonnet, Christelle Maurey, Claire Danel … (2007)

This study sought to assess the cellular and histologic basis of irreversible pulmonary hypertension (PHT) in the clinical setting of congenital heart disease (CHD). Although many children with CHD develop pulmonary vascular disease, it is unclear why this complication is reversible after complete repair in some cases but irreversible in others. Because failure of endothelial cell apoptosis might lead to intimal proliferation and lack of reversibility of PHT, we investigated this and other key markers of vasoactivity and angiogenesis in subjects with PHT and CHD. We assessed antiapoptotic and proapoptotic markers in vascular and perivascular cells in lung biopsy samples from 18 patients with CHD, 7 with reversible and 11 with irreversible PHT, and 6 control patients. Immunostaining for endothelial nitric oxide synthase, vascular endothelial growth factor, and CD34 (markers of vasoactivity and neoangiogenesis) was also performed. The antiapoptotic protein Bcl-2 was highly expressed by pulmonary endothelial cells in all cases of irreversible PHT but in no cases of reversible PHT, nor in control patients (p < 0.001). Intimal proliferation was present in 10 of 11 irreversible PHT cases, but never observed in reversible PHT (p < 0.001). Similarly, perivascular inflammatory T-cells expressed more antiapoptotic proteins in irreversible PHT (p < 0.01). Irreversible PHT cases were also more likely to show compensatory upregulation of vascular endothelial growth factor and new small vessel formation at the sites of native vessel stenosis or occlusion (p < 0.001). Irreversible PHT is strongly associated with impaired endothelial cell apoptosis and antiapoptotic signaling from perivascular inflammatory cells. These changes are associated with intimal proliferation and vessel narrowing, and thereby may contribute to clinical outcomes associated with pulmonary hypertension.

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Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter.

Monique Agrapart, Florent Soubrier, Florence Coulet … (2003)

The human endothelial nitric-oxide synthase gene (heNOS) is constitutively expressed in endothelial cells, and its expression is induced under hypoxia. The goal of this study was to search for regulatory elements of the endothelial nitric-oxide synthase (eNOS) gene responsive to hypoxia. Levels of eNOS mRNA, measured by real time reverse transcriptase-PCR analysis, were increased, and heNOS promoter activity was enhanced by hypoxia as compared with normoxia control experiments. Promoter truncation followed by footprint analysis allowed the mapping and identification of the hypoxia-responsive elements at position -5375 to -5366, closely related to hypoxia-inducible factor (HIF)-responsive element (HRE). To test whether known HIF-1 and HIF-2 are involved in hypoxia-induced heNOS promoter activation, HMEC-1 and HUVEC were transiently transfected with HIF-1alpha and HIF-1beta or HIF-2alpha and HIF-1beta expression vectors. Exogenous HIF-2 markedly increased luciferase reporter activity driven by the heNOS promoter in its native location. The induction of luciferase was conserved with the antisense construct and was increased in cotransfection experiments when this fragment was cloned 5' to the proximal 785-bp fragment of the eNOS promoter. Deletion analysis and site-directed mutagenesis demonstrated that the two contiguous HIF consensus binding sites spanning bp -5375 to -5366 relative to the transcription start site were both functional for heNOS promoter activity induction by hypoxia and by HIF-2 overexpression. In conclusion, we demonstrate that heNOS is a hypoxia-inducible gene, whose transcription is stimulated through HIF-2 interaction with two contiguous HRE sites located at -5375 to -5366 of the heNOS promoter.

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Author and article information

Journal

Journal ID (nlm-ta): Respir Res

Title: Respiratory Research

Publisher: BioMed Central

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Print): 2009

Publication date (Electronic): 13 November 2009

Volume: 10

Issue: 1

Page: 110

Affiliations

[1 ]Neonatology and Pediatric Intensive Care Medicine, Department of General Pediatrics, Heinrich-Heine-University, Duesseldorf, Germany

[2 ]Department of Congenital Heart Disease, University Hospital, Freiburg and Department of Pediatric Cardiology, Deutsches Herzzentrum, Berlin, Germany

[3 ]Department of Pathology, Glasgow Royal Infirmary, Glasgow, UK

[4 ]Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, UK

Article

Publisher ID: 1465-9921-10-110

DOI: 10.1186/1465-9921-10-110

PMC ID: 2780406

PubMed ID: 19912632

SO-VID: 249ba904-8d20-416a-86c2-7342f5f432e9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nitric oxide synthases in infants and children with pulmonary hypertension and congenital heart disease

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Abstract

Rationale

Objectives

Methods

Measurements and main results

Conclusion

Related collections

Biomarkers for Inflammatory Lung Disease

Most cited references 31

Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.

Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease.

Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter.

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