TY  - EJOU
AU  - CHEN, YANG 
AU  - WEN, JUAN 
AU  - HUANG, WEI 
AU  - LI, JIANG 

TI  - NR4A1 enhances glycolysis in hypoxia-exposed pulmonary artery smooth muscle cells by upregulating HIF-1α expression
T2  - BIOCELL

PY  - 2023
VL  - 47
IS  - 11
SN  - 1667-5746

AB  -  <b>Background:</b> Pulmonary arterial hypertension (PAH) is a chronic and progressive disease that is strongly associated with dysregulation of glucose metabolism. Alterations in nuclear receptor subfamily 4 group A member 1 (NR4A1) activity alter the outcome of PAH. This study aimed to investigate the effects of NR4A1 on glycolysis in PAH and its underlying mechanisms. <b>Methods:</b> This study included twenty healthy volunteers and twenty-three PAH patients, and plasma samples were collected from the participants. To mimic the conditions of PAH <i>in vitro</i>, a hypoxia-induced model of pulmonary artery smooth muscle cell (PASMC) model was established. The proliferation of PASMCs was assessed using CCK8 assays. <b>Results:</b> Levels of NR4A1, hypoxia-inducible factor-1α (HIF-1α), and various glycolysis-related enzymes were measured. In addition, extracellular glucose and lactate production were assessed. The interaction between NR4A1 and HIF-1α was evaluated by co-immunoprecipitation assays. Levels of NR4A1 and HIF-1α was increased in PAH patients, and exposure to hypoxia resulted in increased levels of NR4A1 and HIF-1α in PASMCs. NR4A1 interacted with HIF-1α. NR4A1 overexpression enhanced hypoxia-induced expression of HIF-1α, GLUT1, PKM2, HK2, and CD36, decreased glucose levels, increased lactate levels and promoted hypoxic PASMC viability. Conversely, silencing NR4A1 decreased hypoxia-induced expression of HIF-1α, GLUT1, PKM2, HK2, and CD36, promoted glucose production, reduced lactate levels and inhibited hypoxic PASMC viability. Furthermore, overexpression of HIF-1α reversed the regulation of glycolysis caused by NR4A1 knockdown. <b>Conclusion:</b> NR4A1 enhances glycolysis in hypoxia-induced PASMCs by upregulating HIF-1α. Our findings indicate that the management of NR4A1 activity may be a promising strategy for PAH therapy.
KW  - Pulmonary arterial hypertension; NR4A1; HIF-1α; Glycolysis; Hypoxia; Pulmonary arterial smooth muscle cells

DO  - 10.32604/biocell.2023.044459