title: Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation.
abstract: 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.
authors: Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors: Jason
authors: J
authors: Boehme
authors: Department of Medicine, University of Arizona, Tucson, Arizona; and.
authors: Xutong
authors: X
authors: Sun
authors: Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors: Kathryn V
authors: KV
authors: Tormos
authors: Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors: Wenhui
authors: W
authors: Gong
authors: Department of Medicine, University of Arizona, Tucson, Arizona; and.
authors: Manuela
authors: M
authors: Kellner
authors: Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors: Sanjeev A
authors: SA
authors: Datar
authors: Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors: Rebecca Johnson
authors: RJ
authors: Kameny
authors: Department of Medicine, University of Arizona, Tucson, Arizona; and.
authors: Jason X-J
authors: JX
authors: Yuan
authors: Department of Surgery, University of California Davis, Davis, California.
authors: Gary W
authors: GW
authors: Raff
authors: Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors: Jeffrey R
authors: JR
authors: Fineman
authors: Department of Medicine, University of Arizona, Tucson, Arizona; and.
authors: Stephen M
authors: SM
authors: Black
authors: Department of Pediatrics, University of California San Francisco, San Francisco, California; Emin.Maltepe@ucsf.edu.
authors: Emin
authors: E
authors: Maltepe
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006019:Glycolysis; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D055432:Metabolomics; D008928:Mitochondria / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D010101:Oxygen Consumption; D010427:Pentose Phosphate Pathway; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D011652:Pulmonary Circulation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012756:Sheep; D034561:Sheep, Domestic; D013481:Superoxides / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D013481:Superoxides; D019255:NADPH Oxidases
keywords: ROS; glycolysis; mitochondria; oxygen consumption; pulmonary overcirculation