Metabolic and Epigenetic Interactions Regulate Vascular Phenotypic Change and Maintenance in Pulmonary Hypertension
Technical Report,15 Sep 2015,14 Sep 2016
Regents of the University of Colorado Denver Aurora United States
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Changes in metabolism have been suggested to contribute to the aberrant phenotype of vascular cells including fibroblasts in pulmonary hypertension PH. We tested the hypothesis that metabolic reprogramming to aerobic glycolysis is a critical adaptation of fibroblasts in the hypertensive vessel wall that drives proliferative and pro-inflammatory activation through a mechanism involving increased activity of the NADH-sensitive transcriptional co-repressor C-terminal binding protein 1 CtBP1. Using fluorescence-lifetime imaging and mass spectrometry-based metabolomics we found adventitial fibroblasts from animals and humans with severe PH termed PH-Fibs displayed aerobic glycolysis and increased free NADH when cultured under normoxia. We documented increased expression of CtBP1 in vivo and in vitro in fibroblasts within or from the pulmonary adventitia of humans and animals with PH. Decreasing NADH pharmacologically with a novel inhibitor of CtBP1, 4-methylthio-2-oxybutyric acid MTOB, or blocking CtBP1 using siRNA attenuated proliferation, corrected the glycolytic reprogramming phenotype of PH-Fibs, and augmented transcription of anti-proliferative, pro-apoptotic, and anti-inflammatory genes. Treatment of hypoxic mice with MTOB decreased glycolysis, attenuated proliferation, and inflammation and reduced remodeling in the distal pulmonary vasculature. CtBP1 is thus a critical factor linking changes in cell metabolism to cell phenotype in PH and a potential therapeutic target.
- Medicine and Medical Research