Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2013 |
| Outros Autores: | , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/11884 |
Resumo: | Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA. |
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Ong, Peng KaiMelchior, BenoitMartins, Yuri C.Hofer, AnthonyOrjuela-Sánchez, PamelaCabrales, PedroZanini, Graziela M.Frangos, John A.Carvalho, Leonardo J. M.2015-10-07T18:53:03Z2015-10-07T18:53:03Z2013ONG, Peng Kai; et al. Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria. PLoS Pathog, v.9, n.6, e1003444, 11p, 2013.https://www.arca.fiocruz.br/handle/icict/1188410.1371/journal.ppat.1003444engPlos OneNitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malariainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleCenter for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.University of California. Department of Bioengineering. San Diego, CA, USA.Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA / Fundação Oswaldo Cruz. Instituto de pesquisa Clínica Evandro Chagas. Serviço de Parasitologia. Rio de Janeiro, RJ, Brasil.Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre Malária. Rio de Janeiro, RJ, Brasil.Cerebrovascular dysfunction plays a key role in the pathogenesis of cerebral malaria. In experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA, cerebrovascular dysfunction characterized by vascular constriction, occlusion and damage results in impaired perfusion and reduced cerebral blood flow and oxygenation, and has been linked to low nitric oxide (NO) bioavailability. Here, we directly assessed cerebrovascular function in ECM using a novel cranial window method for intravital microscopy of the pial microcirculation and probed the role of NOS isoforms and phosphorylation patterns in the impaired vascular responses. We show that pial arteriolar responses to endothelial NOS (eNOS) and neuronal NOS (nNOS) agonists (Acetylcholine (ACh) and N-Methyl-D-Aspartate (NMDA)) were blunted in mice with ECM, and could be partially recovered by exogenous supplementation of tetrahydrobiopterin (BH4). Pial arterioles in non-ECM mice infected by Plasmodium berghei NK65 remained relatively responsive to the agonists and were not significantly affected by BH4 treatment. These findings, together with the observed blunting of NO production upon stimulation by the agonists, decrease in total NOS activity, augmentation of lipid peroxidation levels, upregulation of eNOS protein expression, and increase in eNOS and nNOS monomerization in the brain during ECM development strongly indicate a state of eNOS/nNOS uncoupling likely mediated by oxidative stress. Furthermore, the downregulation of Serine 1176 (S1176) phosphorylation of eNOS, which correlated with a decrease in cerebrovascular wall shear stress, implicates hemorheological disturbances in eNOS dysfunction in ECM. Finally, pial arterioles responded to superfusion with the NO donor, S-Nitroso-L-glutathione (GSNO), but with decreased intensity, indicating that not only NO production but also signaling is perturbed during ECM. Therefore, the pathological impairment of eNOS and nNOS functions contribute importantly to cerebrovascular dysfunction in ECM and the recovery of intrinsic functionality of NOS to increase NO bioavailability and restore vascular health represents a target for ECM treatment.Cerebral MalariaNitric Oxide Synthase DysfunctionCerebrovascular dysfunctionPlasmodium bergheiMalária CerebralÓxido NítricoDoenças CerebelaresPlasmodium bergheiinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txttext/plain1914https://www.arca.fiocruz.br/bitstream/icict/11884/1/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD51ORIGINALleonardo_carvalho_etal_IOC_2013.pdfapplication/pdf1076079https://www.arca.fiocruz.br/bitstream/icict/11884/2/leonardo_carvalho_etal_IOC_2013.pdf74af087d55ef339c742479670722f02dMD521_leonardo_carvalho_etal_IOC_2013.pdfapplication/pdf1076079https://www.arca.fiocruz.br/bitstream/icict/11884/3/1_leonardo_carvalho_etal_IOC_2013.pdf74af087d55ef339c742479670722f02dMD53TEXTleonardo_carvalho_etal_IOC_2013.pdf.txtleonardo_carvalho_etal_IOC_2013.pdf.txtExtracted texttext/plain64654https://www.arca.fiocruz.br/bitstream/icict/11884/8/leonardo_carvalho_etal_IOC_2013.pdf.txt8760965a8b208a1359408c775a6b0d13MD581_leonardo_carvalho_etal_IOC_2013.pdf.txt1_leonardo_carvalho_etal_IOC_2013.pdf.txtExtracted texttext/plain64654https://www.arca.fiocruz.br/bitstream/icict/11884/9/1_leonardo_carvalho_etal_IOC_2013.pdf.txt8760965a8b208a1359408c775a6b0d13MD59icict/118842022-06-24 13:08:57.141oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352022-06-24T16:08:57Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria |
| title |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria |
| spellingShingle |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria Ong, Peng Kai Cerebral Malaria Nitric Oxide Synthase Dysfunction Cerebrovascular dysfunction Plasmodium berghei Malária Cerebral Óxido Nítrico Doenças Cerebelares Plasmodium berghei |
| title_short |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria |
| title_full |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria |
| title_fullStr |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria |
| title_full_unstemmed |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria |
| title_sort |
Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria |
| author |
Ong, Peng Kai |
| author_facet |
Ong, Peng Kai Melchior, Benoit Martins, Yuri C. Hofer, Anthony Orjuela-Sánchez, Pamela Cabrales, Pedro Zanini, Graziela M. Frangos, John A. Carvalho, Leonardo J. M. |
| author_role |
author |
| author2 |
Melchior, Benoit Martins, Yuri C. Hofer, Anthony Orjuela-Sánchez, Pamela Cabrales, Pedro Zanini, Graziela M. Frangos, John A. Carvalho, Leonardo J. M. |
| author2_role |
author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Ong, Peng Kai Melchior, Benoit Martins, Yuri C. Hofer, Anthony Orjuela-Sánchez, Pamela Cabrales, Pedro Zanini, Graziela M. Frangos, John A. Carvalho, Leonardo J. M. |
| dc.subject.en.pt_BR.fl_str_mv |
Cerebral Malaria Nitric Oxide Synthase Dysfunction Cerebrovascular dysfunction Plasmodium berghei |
| topic |
Cerebral Malaria Nitric Oxide Synthase Dysfunction Cerebrovascular dysfunction Plasmodium berghei Malária Cerebral Óxido Nítrico Doenças Cerebelares Plasmodium berghei |
| dc.subject.decs.pt_BR.fl_str_mv |
Malária Cerebral Óxido Nítrico Doenças Cerebelares Plasmodium berghei |
| description |
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA. |
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2013 |
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2013 |
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2015-10-07T18:53:03Z |
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2015-10-07T18:53:03Z |
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article |
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publishedVersion |
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ONG, Peng Kai; et al. Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria. PLoS Pathog, v.9, n.6, e1003444, 11p, 2013. |
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https://www.arca.fiocruz.br/handle/icict/11884 |
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10.1371/journal.ppat.1003444 |
| identifier_str_mv |
ONG, Peng Kai; et al. Nitric Oxide Synthase Dysfunction Contributes to Impaired Cerebroarteriolar Reactivity in Experimental Cerebral Malaria. PLoS Pathog, v.9, n.6, e1003444, 11p, 2013. 10.1371/journal.ppat.1003444 |
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Plos One |
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Plos One |
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