0472625 - FGÚ 2017 RIV US eng J - Journal Article
Li, M. - Riddle, S. - Zhang, H. - D'Alessandro, A. - Flockton, A. - Serkova, N. J. - Hansen, K. C. - Moldvan, R. - McKeon, B. A. - Frid, M. - Kumar, S. - Li, H. - Liu, H. - Canovas, A. - Medrano, J. F. - Thomas, M. G. - Iloska, D. - Plecitá-Hlavatá, Lydie - Ježek, Petr - Pullamsetti, S. - Fini, M. A. - El Kasmi, K. C. - Zhang, Q. H. - Stenmark, K. R.
Metabolic Reprogramming Regulates the Proliferative and Inflammatory Phenotype of Adventitial Fibroblasts in Pulmonary Hypertension Through the Transcriptional Corepressor C-Terminal Binding Protein-1.
Circulation. Roč. 134, č. 15 (2016), s. 1105-1121. ISSN 0009-7322. E-ISSN 1524-4539
R&D Projects: GA MŠMT(CZ) LH11055; GA MŠMT(CZ) LH15071
Institutional support: RVO:67985823
Keywords : arterial fibroblasts * pulmonary hypertension * metabolism * CtBP1
Subject RIV: ED - Physiology
Impact factor: 19.309, year: 2016

We found that adventitial fibroblasts from calves with severe hypoxia-induced PH and humans with idiopathic pulmonary arterial hypertension (PH-Fibs) displayed aerobic glycolysis when cultured under normoxia, accompanied by increased free NADH and NADH/NAD(+) ratios. Expression of the NADH sensor CtBP1 was increased in vivo and in vitro in fibroblasts within the pulmonary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with PH and cultured PH-Fibs, respectively. Decreasing NADH pharmacologically with MTOB or genetically blocking CtBP1 with siRNA upregulated the cyclin-dependent genes (p15 and p21) and proapoptotic regulators (NOXA and PERP), attenuated proliferation, corrected the glycolytic reprogramming phenotype of PH-Fibs, and augmented transcription of the anti-inflammatory gene HMOX1. Chromatin immunoprecipitation analysis demonstrated that CtBP1 directly binds the HMOX1 promoter. Treatment of hypoxic mice with MTOB decreased glycolysis and expression of inflammatory genes, attenuated proliferation, and suppressed macrophage numbers and remodeling in the distal pulmonary vasculature.
Permanent Link: http://hdl.handle.net/11104/0269881