The effect of acidosis on pulmonary vascular smooth muscle cell metabolic response to hypoxia: implications for Pulmonary Hypertension

Abstract

Background A glycolytic shift is key to apoptotic resistance in cancer cells and pulmonary vascular smooth muscle cells in pulmonary hypertension (PH). Its reversal may lead to apoptosis and reverse pulmonary vascular remodeling. We found that acidosis reversed remodeling in experimental PH and sought to investigate the metabolic response of pulmonary artery smooth muscle cells (PASMCs) to hypoxia. Materials and Methods We exposed rats to hypoxia to develop PH; acidosis was induced by ammonium chloride (NH4Cl) in drinking water. Primary PASMCs were exposed to acidosis (pH 6.8), physiologic pH (7.4) or hypoxia. Glucose Transporter-1 (Glut-1) mRNA and protein were assessed in lungs and PASMCs. Mitochondrial membrane potential (MMP) and apoptosis were assessed by JC-1 and caspase-3 cleavage, respectively. Results Glut-1 mRNA increased in lungs of hypoxic animals compared to normoxic with a decrease in hypoxic animals treated with NH4Cl. Isolated PASMCs showed higher Glut-1 mRNA in hypoxia than normoxia at physiologic and acidic pH. Acidic pH decreased Glut-1 protein in normoxia and hypoxia. Exposure to acidic pH decreased MMP and increased apoptosis by hydrogen peroxide. Conclusions Acidosis results in decreased Glut-1 in lungs and PASMCs, a decreased MMP and increased propensity to apoptosis. We speculate that acidosis reverses the glycolytic phenotype in hypoxia, thus promoting an apoptotic phenotype. Supported by NIH grant: 5T32HD007466