We are analyzing https://link.springer.com/article/10.1007/s00109-011-0762-2.

Title:
Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension | Journal of Molecular Medicine
Description:
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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article, pubmed, google, scholar, pulmonary, cas, hypertension, cell, arterial, tnfα, cells, bonnet, michelakis, vascular, med, haromy, pah, inflammatory, sutendra, pasmc, human, access, mol, apoptosis, artery, smooth, muscle, mitochondrial, activity, physiol, privacy, cookies, content, journal, medicine, pyruvate, dehydrogenase, dromparis, remodeling, decreased, pdh, factor, sci, lung, publish, search, mcmurtry, evangelos, activation, activated,

Topics {✒️}

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         headline:Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension
         description: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.
         datePublished:2011-08-02T00:00:00Z
         dateModified:2011-08-02T00:00:00Z
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            Inflammation
            Apoptosis
            Metabolism
            Mitochondria
            Molecular Medicine
            Human Genetics
            Internal Medicine
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      headline:Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension
      description: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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         Inflammation
         Apoptosis
         Metabolism
         Mitochondria
         Molecular Medicine
         Human Genetics
         Internal Medicine
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