Cargando…

Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats

BACKGROUND: Simvastatin has been shown to ameliorate pulmonary hypertension by several mechanisms in experimental animal models. In this study, we hypothesized that the major benefits of simvastatin in pulmonary hypertension occur via the heme oxygenase-1 pathway. METHODS: Simvastatin (10 mg/kgw/day...

Descripción completa

Detalles Bibliográficos
Autores principales: Hsu, Hsao-Hsun, Ko, Wen-Je, Hsu, Jo-Yu, Chen, Jin-Shing, Lee, Yung-Chie, Lai, I-Rue, Chen, Chau-Fong
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681458/
https://www.ncbi.nlm.nih.gov/pubmed/19409105
http://dx.doi.org/10.1186/1465-9921-10-32
_version_ 1782167032610947072
author Hsu, Hsao-Hsun
Ko, Wen-Je
Hsu, Jo-Yu
Chen, Jin-Shing
Lee, Yung-Chie
Lai, I-Rue
Chen, Chau-Fong
author_facet Hsu, Hsao-Hsun
Ko, Wen-Je
Hsu, Jo-Yu
Chen, Jin-Shing
Lee, Yung-Chie
Lai, I-Rue
Chen, Chau-Fong
author_sort Hsu, Hsao-Hsun
collection PubMed
description BACKGROUND: Simvastatin has been shown to ameliorate pulmonary hypertension by several mechanisms in experimental animal models. In this study, we hypothesized that the major benefits of simvastatin in pulmonary hypertension occur via the heme oxygenase-1 pathway. METHODS: Simvastatin (10 mg/kgw/day) was tested in two rat models of pulmonary hypertension (PH): monocrotaline administration and chronic hypoxia. The hemodynamic changes, right heart hypertrophy, HO-1 protein expression, and heme oxygenase (HO) activity in lungs were measured in both models with and without simvastatin treatment. Tin-protoporphyrin (SnPP, 20 μmol/kg w/day), a potent inhibitor of HO activity, was used to confirm the role of HO-1. RESULTS: Simvastatin significantly ameliorated pulmonary arterial hypertension from 38.0 ± 2.2 mm Hg to 22.1 ± 1.9 mm Hg in monocrotaline-induced PH (MCT-PH) and from 33.3 ± 0.8 mm Hg to 17.5 ± 2.9 mm Hg in chronic hypoxia-induced PH (CH-PH) rats. The severity of right ventricular hypertrophy was significantly reduced by simvastatin in MCT-PH and CH-PH rats. Co-administration with SnPP abolished the benefits of simvastatin. Simvastatin significantly increased HO-1 protein expression and HO activity in the lungs of rats with PH; however co-administration of SnPP reduced HO-1 activity only. These observations indicate that the simvastatin-induced amelioration of pulmonary hypertension was directly related to the activity of HO-1, rather than its expression. CONCLUSION: This study demonstrated that simvastatin treatment ameliorates established pulmonary hypertension primarily through an HO-1-dependent pathway.
format Text
id pubmed-2681458
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-26814582009-05-14 Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats Hsu, Hsao-Hsun Ko, Wen-Je Hsu, Jo-Yu Chen, Jin-Shing Lee, Yung-Chie Lai, I-Rue Chen, Chau-Fong Respir Res Research BACKGROUND: Simvastatin has been shown to ameliorate pulmonary hypertension by several mechanisms in experimental animal models. In this study, we hypothesized that the major benefits of simvastatin in pulmonary hypertension occur via the heme oxygenase-1 pathway. METHODS: Simvastatin (10 mg/kgw/day) was tested in two rat models of pulmonary hypertension (PH): monocrotaline administration and chronic hypoxia. The hemodynamic changes, right heart hypertrophy, HO-1 protein expression, and heme oxygenase (HO) activity in lungs were measured in both models with and without simvastatin treatment. Tin-protoporphyrin (SnPP, 20 μmol/kg w/day), a potent inhibitor of HO activity, was used to confirm the role of HO-1. RESULTS: Simvastatin significantly ameliorated pulmonary arterial hypertension from 38.0 ± 2.2 mm Hg to 22.1 ± 1.9 mm Hg in monocrotaline-induced PH (MCT-PH) and from 33.3 ± 0.8 mm Hg to 17.5 ± 2.9 mm Hg in chronic hypoxia-induced PH (CH-PH) rats. The severity of right ventricular hypertrophy was significantly reduced by simvastatin in MCT-PH and CH-PH rats. Co-administration with SnPP abolished the benefits of simvastatin. Simvastatin significantly increased HO-1 protein expression and HO activity in the lungs of rats with PH; however co-administration of SnPP reduced HO-1 activity only. These observations indicate that the simvastatin-induced amelioration of pulmonary hypertension was directly related to the activity of HO-1, rather than its expression. CONCLUSION: This study demonstrated that simvastatin treatment ameliorates established pulmonary hypertension primarily through an HO-1-dependent pathway. BioMed Central 2009 2009-05-02 /pmc/articles/PMC2681458/ /pubmed/19409105 http://dx.doi.org/10.1186/1465-9921-10-32 Text en Copyright © 2009 Hsu et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 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.
spellingShingle Research
Hsu, Hsao-Hsun
Ko, Wen-Je
Hsu, Jo-Yu
Chen, Jin-Shing
Lee, Yung-Chie
Lai, I-Rue
Chen, Chau-Fong
Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
title Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
title_full Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
title_fullStr Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
title_full_unstemmed Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
title_short Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
title_sort simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681458/
https://www.ncbi.nlm.nih.gov/pubmed/19409105
http://dx.doi.org/10.1186/1465-9921-10-32
work_keys_str_mv AT hsuhsaohsun simvastatinamelioratesestablishedpulmonaryhypertensionthroughahemeoxygenase1dependentpathwayinrats
AT kowenje simvastatinamelioratesestablishedpulmonaryhypertensionthroughahemeoxygenase1dependentpathwayinrats
AT hsujoyu simvastatinamelioratesestablishedpulmonaryhypertensionthroughahemeoxygenase1dependentpathwayinrats
AT chenjinshing simvastatinamelioratesestablishedpulmonaryhypertensionthroughahemeoxygenase1dependentpathwayinrats
AT leeyungchie simvastatinamelioratesestablishedpulmonaryhypertensionthroughahemeoxygenase1dependentpathwayinrats
AT laiirue simvastatinamelioratesestablishedpulmonaryhypertensionthroughahemeoxygenase1dependentpathwayinrats
AT chenchaufong simvastatinamelioratesestablishedpulmonaryhypertensionthroughahemeoxygenase1dependentpathwayinrats