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Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension

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Abstract

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 and Affiliations

  1. Department of Medicine (Pulmonary Hypertension Program), University of Alberta, Edmonton, Canada

    Gopinath Sutendra, Peter Dromparis, Alois Haromy, Michael S. McMurtry & Evangelos D. Michelakis

  2. Department of Biochemistry, University of Alberta, Edmonton, Canada

    R. Chris Bleackley

  3. Department of Medicine (Cardiology), University of Alberta, Edmonton, Canada, T6G2B7

    Evangelos D. Michelakis

  4. Department of Medicine, Laval University, Quebec City, QC, Canada

    Sébastien Bonnet

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  1. Gopinath Sutendra
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  2. Peter Dromparis
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Correspondence to Evangelos D. Michelakis.

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Sutendra, G., Dromparis, P., Bonnet, S. et al. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension. J Mol Med 89, 771–783 (2011). https://doi.org/10.1007/s00109-011-0762-2

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  • DOI: https://doi.org/10.1007/s00109-011-0762-2

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