Abstract
The molecular mechanisms underlying the metabolic shift toward increased glycolysis observed in pulmonary artery smooth muscle cells (PASMC) during the pathogenesis of pulmonary arterial hypertension (PAH) are not fully understood. Here we show that the glycolytic enzyme α-enolase (ENO1) regulates the metabolic reprogramming and malignant phenotype of PASMC. We show that ENO1 levels are elevated in patients with associated PAH and in animal models of hypoxic pulmonary hypertension (HPH). The silencing or inhibition of ENO1 decreases PASMC proliferation and de-differentiation, and induces PASMC apoptosis, whereas the overexpression of ENO1 promotes a synthetic, de- differentiated, and apoptotic-resistant phenotype via the AMPK-Akt pathway. The suppression of ENO1 prevents the hypoxia-induced metabolic shift from mitochondrial respiration to glycolysis in PASMC. Finally, we find that pharmacological inhibition of ENO1 reverses HPH in mice and rats, suggesting ENO1 as a regulator of pathogenic metabolic reprogramming in HPH.
Highlights
The molecular mechanisms underlying the metabolic shift toward increased glycolysis observed in pulmonary artery smooth muscle cells (PASMC) during the pathogenesis of pulmonary arterial hypertension (PAH) are not fully understood
We found that PASMC isolated from associated PAH (APAH) patients but not from patients of idiopathic PAH (IPAH), expressed markedly increased protein levels of ENO1 (Fig. 1a, b)
ENO1 was ubiquitously expressed in the lung sections of PAH patients, including the media, intima, and the perivascular region, suggesting the expression of ENO1 in PASMC, endothelial cells, and monocyte/macrophages, it was mainly elevated in the media of the APAH patients (Fig. 1d)
Summary
The molecular mechanisms underlying the metabolic shift toward increased glycolysis observed in pulmonary artery smooth muscle cells (PASMC) during the pathogenesis of pulmonary arterial hypertension (PAH) are not fully understood. PASMC from animal models of pulmonary hypertension (PH) and human tissues with PAH exhibit a consistent pattern of reprogrammed cellular metabolism, which closely aligns with the Warburg effect in cancers[3] In these cells, mitochondrial glucose oxidation is suppressed, whereas glycolysis is upregulated as the major source of adenosine triphosphate production. Silencing of ENO1 in cancer cells promotes the adaptation to catabolic pathways, restores acetyl-CoA bulk through enhanced β-oxidation, and fuels the tricarboxylic acid (TCA) cycle by the cataplerotic reactions of tyrosine and glutamine catabolism[12,13]. It remains unknown whether ENO participates in the metabolic reprogramming of PASMC in PAH. Our study provides evidence that ENO1 regulates metabolic reprogramming in PAH
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