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http://purl.uniprot.org/citations/16735674http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/16735674http://www.w3.org/2000/01/rdf-schema#comment"

Background

The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain.

Methods and results

Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1. PAH began after 20 weeks of age, causing death by &60 weeks. FHR/BN1 did not develop PAH. FHR pulmonary arterial smooth muscle cells (PASMCs) had a rarified reticulum of hyperpolarized mitochondria with reduced expression of electron transport chain components and superoxide dismutase-2. These mitochondrial abnormalities preceded PAH and persisted in culture. Depressed mitochondrial reactive oxygen species (ROS) production caused normoxic activation of hypoxia inducible factor (HIF-1alpha), which then inhibited expression of oxygen-sensitive, voltage-gated K+ channels (eg, Kv1.5). Disruption of this mitochondrial-HIF-Kv pathway impaired oxygen sensing (reducing hypoxic pulmonary vasoconstriction, causing polycythemia), analogous to the pathophysiology of chronically hypoxic Sprague-Dawley rats. Restoring ROS (exogenous H2O2) or blocking HIF-1alpha activation (dominant-negative HIF-1alpha) restored Kv1.5 expression/function. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, corrected the mitochondrial-HIF-Kv pathway in FHR-PAH and human PAH PASMCs. Oral dichloroacetate regressed FHR-PAH and polycythemia, increasing survival. Chromosome 1 genes that were dysregulated in FHRs and relevant to the mitochondria-HIF-Kv pathway included HIF-3alpha (an HIF-1alpha repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1alpha activation; and reduced expression/activity of HIF-3alpha, cytochrome c oxidase, and superoxide dismutase-2.

Conclusions

FHRs have a chromosome 1 abnormality that disrupts a mitochondria-ROS-HIF-Kv pathway, leading to PAH. Similar abnormalities occur in idiopathic human PAH. This study reveals an intersection between oxygen-sensing mechanisms and PAH. The mitochondria-ROS-HIF-Kv pathway offers new targets for PAH therapy."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.105.609008"xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Porter C.J."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Andrade-Navarro M.A."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Bonnet S."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Michelakis E.D."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Archer S.L."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Weir E.K."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Bonnet S.'"xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Haromy A."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Harry G."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Thebaud B."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"Moudgil R."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/author"McMurtry M.S."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/date"2006"xsd:gYear
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/name"Circulation"xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/pages"2630-2641"xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/title"An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension."xsd:string
http://purl.uniprot.org/citations/16735674http://purl.uniprot.org/core/volume"113"xsd:string
http://purl.uniprot.org/citations/16735674http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/16735674
http://purl.uniprot.org/citations/16735674http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/16735674
http://purl.uniprot.org/uniprot/O35800#attribution-267BA6570A297A851641FF936D2B923Bhttp://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/16735674
http://purl.uniprot.org/uniprot/P19024#attribution-267BA6570A297A851641FF936D2B923Bhttp://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/16735674
http://purl.uniprot.org/uniprot/#_D4A8P8-mappedCitation-16735674http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/16735674
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