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Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation.
Boehme, Jason; Sun, Xutong; Tormos, Kathryn V; Gong, Wenhui; Kellner, Manuela; Datar, Sanjeev A; Kameny, Rebecca Johnson; Yuan, Jason X-J; Raff, Gary W; Fineman, Jeffrey R; Black, Stephen M; Maltepe, Emin.
Afiliación
  • Boehme J; Department of Pediatrics, University of California San Francisco, San Francisco, California.
  • Sun X; Department of Medicine, University of Arizona, Tucson, Arizona; and.
  • Tormos KV; Department of Pediatrics, University of California San Francisco, San Francisco, California.
  • Gong W; Department of Pediatrics, University of California San Francisco, San Francisco, California.
  • Kellner M; Department of Medicine, University of Arizona, Tucson, Arizona; and.
  • Datar SA; Department of Pediatrics, University of California San Francisco, San Francisco, California.
  • Kameny RJ; Department of Pediatrics, University of California San Francisco, San Francisco, California.
  • Yuan JX; Department of Medicine, University of Arizona, Tucson, Arizona; and.
  • Raff GW; Department of Surgery, University of California Davis, Davis, California.
  • Fineman JR; Department of Pediatrics, University of California San Francisco, San Francisco, California.
  • Black SM; Department of Medicine, University of Arizona, Tucson, Arizona; and.
  • Maltepe E; Department of Pediatrics, University of California San Francisco, San Francisco, California; Emin.Maltepe@ucsf.edu.
Am J Physiol Heart Circ Physiol ; 311(4): H944-H957, 2016 10 01.
Article en En | MEDLINE | ID: mdl-27591215
Vascular cell hyperproliferation and metabolic reprogramming contribute to the pathophysiology of pulmonary arterial hypertension (PAH). An important cause of PAH in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To better characterize this disease course we studied early changes in pulmonary artery smooth muscle cell (PASMC) proliferation and metabolism using a unique ovine model of pulmonary overcirculation. Consistent with PAH in adults, PASMCs derived from 4-wk-old lambs exposed to increased PBF (shunt) exhibited increased rates of proliferation. While shunt PASMCs also exhibited significant decreases in mitochondrial oxygen consumption, membrane potential, and tricarboxylic acid (TCA) cycle function, suggesting a switch to Warburg metabolism as observed in advanced PAH in adults, they unexpectedly demonstrated decreased glycolytic lactate production, likely due to enhanced flux through the pentose phosphate pathway (PPP). This may be a response to the marked increase in NADPH oxidase (Nox) activity and decreased NADPH/NADP+ ratios observed in shunt PASMCs. Consistent with these findings, pharmacological inhibition of Nox activity preferentially slowed the growth of shunt PASMCs in vitro. Our results therefore indicate that PASMC hyperproliferation is observed early in the setting of pulmonary overcirculation and is accompanied by a unique metabolic profile that is independent of HIF-1α, PDHK1, or increased glycolytic flux. Our results also suggest that Nox inhibition may help prevent pulmonary overcirculation-induced PAH in children born with CHD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vía de Pentosa Fosfato / Arteria Pulmonar / NADPH Oxidasas / Miocitos del Músculo Liso / Proliferación Celular / Hipertensión Pulmonar / Mitocondrias / Músculo Liso Vascular Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Am J Physiol Heart Circ Physiol Asunto de la revista: CARDIOLOGIA / FISIOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vía de Pentosa Fosfato / Arteria Pulmonar / NADPH Oxidasas / Miocitos del Músculo Liso / Proliferación Celular / Hipertensión Pulmonar / Mitocondrias / Músculo Liso Vascular Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Am J Physiol Heart Circ Physiol Asunto de la revista: CARDIOLOGIA / FISIOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos