Abstract 640: PASMC Hyperproliferation and Metabolic Shift in a Model of Pulmonary Overcirculation
BACKGROUND: Pulmonary arterial hypertension (PAH) is a complex disease that lacks adequate therapies. Recognition that endothelial and smooth muscle cell hyper-proliferation contribute to the pathophysiology has drawn parallels to cancer biology and highlighted shared alterations in growth signaling and metabolism. Similar to the Warburg Effect described in malignancies, smooth muscle and endothelial cells exhibit a phenotype of aerobic glycolysis in the setting of PAH.
Objective: We hypothesize that in an animal model of increased pulmonary blood flow and early pulmonary vascular disease, smooth muscle cells from the central pulmonary arteries will exhibit metabolic alterations similar to the Warburg Effect.
DESIGN/METHODS: Fetal lambs underwent surgical placement of an aortopulmonary shunt resulting in a postnatal increase in pulmonary blood flow. Smooth muscle cells (PASMCs) from the central PAs were isolated for analysis. Extracellular flux analysis was used to measure concurrent oxygen consumption and extracellular acidification. Targeted metabolites were measured using HPLC-mass spectrometry.
Results: PASMCs from the shunted animals exhibit faster growth and a shorter calculated doubling time (29.5 vs. 45.2 hours). PASMCs derived from shunted animals had a 55% decrease in oxygen consumption rate and a 59% decrease in extracellular acidification rate. This is accompanied by a relative decrease in the mitochondrial membrane potential in the shunt cells compared to controls. Metabolic analysis shows increases in the PPP metabolites erythritol, S7P and R5P/X5P, decreases in the glycolytic metabolites Fru1,6BP and PEP, decreased malate in the TCA cycle and accumulation of acetyl-CoA in shunted cells compared to controls.
Conclusions: PASMCs from lambs with pulmonary overcirculation and early PAH have a phenotype of hyper-proliferation and altered metabolism. The low rate of oxygen consumption and extracellular acidification suggest concurrent decreases of both mitochondrial respiration and glycolytic flux. Targeted metabolite analysis suggests increased glucose entry into the pentose phosphate shunt rather than glycolysis and relative depletion of TCA cycle intermediates may underlie these observed changes.
Author Disclosures: J. Boehme: None. K. Tormos: None. J. Fineman: None. E. Maltepe: None.
- © 2015 by American Heart Association, Inc.