Extracellular Acidosis Alters the Metabolic Phenotype and Susceptibility to Apoptosis of Pulmonary Artery Smooth Muscle Cells

Aims: A metabolic shift from oxidative phosphorylation to glycolysis confers resistance to apoptosis in pulmonary artery smooth muscle cells (PASMCs) in pulmonary hypertension (PH). Its reversal may promote a pro-apoptotic phenotype and reverse pulmonary vascular remodeling. We previously showed that metabolic acidosis 142 Adriana Geldart et al in vivo reversed remodeling in experimental PH and sought to investigate the effect of extracellular acidosis (EA) on the metabolic phenotype of PASMCs. Methods and Results: Primary PASMCs were exposed to acidosis (pH 6.8) or physiologic pH (7.4) in normoxia or hypoxia. Adult male Sprague Dawley rats were exposed to hypoxia to develop PH. Metabolic acidosis was induced in vivo with ammonium 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-1 and Hex-II protein levels were increased in lungs of hypoxic animals and PASMCs exposed to hypoxia, while treatment with NH4Cl in vivo or EA in vitro attenuated this response. Acidic pH decreased lactate production and proliferation in PASMCs and increased susceptibility to apoptosis as evidenced by a higher percentage of cells with lower MMP and increased caspase-3 cleavage in response to hydrogen peroxide. Conclusions: Acidosis attenuates the hypoxic induction of key enzymes for glucose uptake and glycolysis in PASMCs and lungs, decreases proliferation and increases susceptibility to apoptosis in PASMCs. We speculate that these effects of acidosis on PASMC metabolic phenotype may underlie acidosis-induced reversal of pulmonary vascular remodeling in experimental PH.