| Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension. | |
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MedLine Citation:
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PMID: 21809123 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Gopinath Sutendra; Peter Dromparis; Sébastien Bonnet; Alois Haromy; Michael S McMurtry; R Chris Bleackley; Evangelos D Michelakis |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-2 |
Journal Detail:
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Title: Journal of molecular medicine (Berlin, Germany) Volume: - ISSN: 1432-1440 ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-2 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9504370 Medline TA: J Mol Med (Berl) Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Medicine (Pulmonary Hypertension Program), University of Alberta, Edmonton, Canada. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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