title: Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension.
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.
authors.affiliation: Department of Medicine (Pulmonary Hypertension Program), University of Alberta, Edmonton, Canada.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.forename: Peter
authors.initials: P
authors.lastname: Dromparis
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Michael S
authors.initials: MS
authors.lastname: McMurtry
authors.forename: R Chris
authors.initials: RC
authors.lastname: Bleackley
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000818:Animals; D000068800:Etanercept; D065627:Familial Primary Pulmonary Hypertension; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051666:Kv1.5 Potassium Channel / Q000378:metabolism; D008954:Models, Biological; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D007074:Immunoglobulin G; D018836:Inflammation Mediators; D051666:Kv1.5 Potassium Channel; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016686:Monocrotaline; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000068800:Etanercept