| http://purl.uniprot.org/citations/21809123 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/21809123 | http://www.w3.org/2000/01/rdf-schema#comment | "Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMC). This apoptosis resistance is characterized by PASMC mitochondrial hyperpolarization [in part, due to decreased pyruvate dehydrogenase (PDH) activity], decreased mitochondrial reactive oxygen species (mROS), downregulation of Kv1.5, increased [Ca(++)](i), and activation of the transcription factor nuclear factor of activated T cells (NFAT). Inflammatory cells are present within and around the remodeled arteries and patients with PAH have elevated levels of inflammatory cytokines, including tumor necrosis factor-α (TNFα). We hypothesized that the inflammatory cytokine TNFα inhibits PASMC PDH activity, inducing a PAH phenotype in normal PASMC. We exposed normal human PASMC to recombinant human TNFα and measured PDH activity. In TNFα-treated cells, PDH activity was significantly decreased. Similar to exogenous TNFα, endogenous TNFα secreted from activated human CD8(+) T cells, but not quiescent T cells, caused mitochondrial hyperpolarization, decreased mROS, decreased K(+) current, increased [Ca(++)](i), and activated NFAT in normal human PASMC. A TNFα antibody completely prevented, while recombinant TNFα mimicked the T cell-induced effects. In vivo, the TNFα antagonist etanercept prevented and reversed monocrotaline (MCT)-induced PAH. In a separate model, T cell deficient rats developed less severe MCT-induced PAH compared to their controls. We show that TNFα can inhibit PASMC PDH activity and induce a PAH phenotype. Our work supports the use of anti-inflammatory therapies for PAH."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.org/dc/terms/identifier | "doi:10.1007/s00109-011-0762-2"xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/author | "Sutendra G."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/author | "Bleackley R.C."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/author | "Bonnet S."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/author | "Michelakis E.D."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/author | "Haromy A."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/author | "McMurtry M.S."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/author | "Dromparis P."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/date | "2011"xsd:gYear |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/name | "J Mol Med (Berl)"xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/pages | "771-783"xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/title | "Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFalpha contributes to the pathogenesis of pulmonary arterial hypertension."xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://purl.uniprot.org/core/volume | "89"xsd:string |
| http://purl.uniprot.org/citations/21809123 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/21809123 |
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