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Extracellular acidosis alters the metabolic phenotype and susceptibility to apoptosis of pulmonary artery smooth muscle cells

Author(s): A. Geldart | J. D. Fessenden | E. Arons | S. A. Mitsialis | S. Kourembanas | H. Christou

Journal: Clinical and Experimental Medical Sciences
ISSN 1314-7528

Volume: 1;
Issue: 3;
Start page: 141;
Date: 2013;
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Keywords: Pulmonary Hypertension | Hexokinase-II | Glucose transporter-1 | vascular remodeling

Aims: A metabolic shift from oxidative phosphorylation to glycolysis confersresistance to apoptosis in pulmonary artery smooth muscle cells (PASMCs) inpulmonary hypertension (PH). Its reversal may promote a pro-apoptotic phenotype andreverse pulmonary vascular remodeling. We previously showed that metabolic acidosis in vivo reversed remodeling in experimental PH and sought to investigate the effect ofextracellular acidosis (EA) on the metabolic phenotype of PASMCs.Methods and Results: Primary PASMCs were exposed to acidosis (pH 6.8) orphysiologic pH (7.4) in normoxia or hypoxia. Adult male Sprague Dawley rats wereexposed to hypoxia to develop PH. Metabolic acidosis was induced in vivo withammonium chloride (NH4Cl). We analyzed the abundance of Glucose Transporter-1(Glut-1) and Hexokinase-II (Hex-II) in PASMCs and lungs and lactate levels,mitochondrial membrane potential (MMP) and caspase-3 cleavage in PASMCs. Glut-1and Hex-II protein levels were increased in lungs of hypoxic animals and PASMCsexposed to hypoxia, while treatment with NH4Cl in vivo or EA in vitro attenuated thisresponse. Acidic pH decreased lactate production and proliferation in PASMCs andincreased susceptibility to apoptosis as evidenced by a higher percentage of cells withlower MMP and increased caspase-3 cleavage in response to hydrogen peroxide.Conclusions: Acidosis attenuates the hypoxic induction of key enzymes for glucoseuptake and glycolysis in PASMCs and lungs, decreases proliferation and increasessusceptibility to apoptosis in PASMCs. We speculate that these effects of acidosis onPASMC metabolic phenotype may underlie acidosis-induced reversal of pulmonaryvascular remodeling in experimental PH.

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