title: Glucose-6-phosphate dehydrogenase plays a critical role in hypoxia-induced CD133+ progenitor cells self-renewal and stimulates their accumulation in the lungs of pulmonary hypertensive rats.
abstract: Although hypoxia is detrimental to most cell types, it aids survival of progenitor cells and is associated with diseases like cancer and pulmonary hypertension in humans. Therefore, understanding the underlying mechanisms that promote survival of progenitor cells in hypoxia and then developing novel therapies to stop their growth in hypoxia-associated human diseases is important. Here we demonstrate that the proliferation and growth of human CD133(+) progenitor cells, which contribute to tumorigenesis and the development of pulmonary hypertension, are increased when cultured under hypoxic conditions. Furthermore, glucose-6-phosphate dehydrogenase (G6PD) activity was increased threefold in hypoxic CD133(+) cells. The increased G6PD activity was required for CD133(+) cell proliferation, and their growth was arrested by G6PD inhibition or knockdown. G6PD activity upregulated expression of HIF1α, cyclin A, and phospho-histone H3, thereby promoting CD133(+) cell dedifferentiation and self-renewal and altering cell cycle regulation. When CD133(+) cells were cocultured across a porous membrane from pulmonary artery smooth muscle cells (PASMCs), G6PD-dependent H2O2 production and release by PASMCs recruited CD133(+) cells to the membrane, where they attached and expressed smooth muscle markers (α-actin and SM22α). Inhibition of G6PD reduced smooth muscle marker expression in CD133(+) cells under normoxia but not hypoxia. In vivo, CD133(+) cells colocalized with G6PD(+) cells in the perivascular region of lungs from rats with hypoxia-induced pulmonary hypertension. Finally, inhibition of G6PD by dehydroepiandrosterone in pulmonary arterial hypertensive rats nearly abolished CD133(+) cell accumulation around pulmonary arteries and the formation of occlusive lesions. These observations suggest G6PD plays a key role in increasing hypoxia-induced CD133(+) cell survival in hypertensive lungs that differentiate to smooth muscle cells and contribute to pulmonary arterial remodeling during development of pulmonary hypertension.
authors: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama;
authors: Sukrutha
authors: S
authors: Chettimada
authors: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama;
authors: Sachindra Raj
authors: SR
authors: Joshi
authors: Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama;
authors: Abdallah
authors: A
authors: Alzoubi
authors: Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama; and.
authors: Sarah A
authors: SA
authors: Gebb
authors: Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors: Ivan F
authors: IF
authors: McMurtry
authors: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama; sachin_gupte@yahoo.com s_gupte@nymc.edu.
authors: Rakhee
authors: R
authors: Gupte
authors: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors: Sachin A
authors: SA
authors: Gupte
mesh_terms: D000071916:AC133 Antigen; D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002454:Cell Differentiation; D015687:Cell Hypoxia; D049109:Cell Proliferation; D018920:Coculture Techniques; D003687:Dehydroepiandrosterone / Q000008:administration & dosage; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D010455:Peptides / Q000378:metabolism*; D021381:Protein Transport; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000201:enzymology* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000606023:PROM1 protein, human; D010455:Peptides; C000606025:Prom1 protein, rat; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D003687:Dehydroepiandrosterone; D005954:Glucosephosphate Dehydrogenase
keywords: HIF; Notch; cell cycle; cyclin A; dedifferentiation; pentose phosphate pathway; phenotype; phospho-histone H3; pulmonary artery smooth muscle cells; pulmonary hypertension