Targeting Endothelial ENO1 (Alpha-Enolase) -PI3K-Akt-mTOR Axis Alleviates Hypoxic Pulmonary Hypertension

Abstract

Background: It has been shown that glycolytic protein alpha-ENO1 (enolase) contributes to the pathogenesis of pulmonary hypertension through acting smooth muscle cells; however, the roles of ENO1-caused endothelial and mitochondrial dysfunctions in Group 3 pulmonary hypertension remain unexplored. Methods: PCR array and RNA sequencing were used to screen and decipher the differential gene expression by hypoxia-treated ECs. Techniques of small-interfering RNA, specific inhibitor and plasmids carrying gene of ENO1, interventions with specific inhibitor and AAV-ENO1 delivery were employed to explore the role of ENO1 in hypoxic pulmonary hypertension in vitro and in vivo, respectively. Assays for cell proliferation, angiogenesis, and adhesion were employed to analyze cell behaviors, while seahorse analysis was used to measure mitochondrial function of human pulmonary artery endothelial cells. Results: PCR array data showed that ENO1 expression increased in human pulmonary artery endothelial cells exposed to hypoxia, as well as in lung tissues from patients with chronic obstructive lung disease-pulmonary hypertension and murine model of hypoxic pulmonary hypertension. Inhibition of ENO1 restored the hypoxia-induced endothelial dysfunction, including excessive proliferation, angiogenesis, and adhesion, while overexpression of ENO1 promotes these disorders of human pulmonary artery endothelial cells. RNA-seq showed that ENO1 targets mitochondrion-related genes and PI3K-Akt signaling pathway. Mice treated with ENO1 inhibitor exhibited ameliorated pulmonary hypertension and improved right ventricular failure induced by hypoxia. A reversal effect was observed in mice exposed to hypoxia and inhaled adenoassociated virus overexpressing ENO1. Conclusions: These results indicate that hypoxic pulmonary hypertension is associated with an increased level of ENO1 and that targeting ENO1 might reduce experimental hypoxic pulmonary hypertension by improving endothelial and mitochondrial dysfunction via PI3K-Akt-mTOR signaling pathway.

Identification of Emerging Drug Targets for Pulmonary Functions Through Mendelian Randomization Analysis of the Plasma Proteome

“…As part of the broblast growth factor receptor family, FGFR1 improves pulmonary function via signaling pathways like PI3K in pulmonary hypertension and MAPK in COPD. [26,27] Especially noteworthy is the heightened expression of basic broblast growth factors in the bronchial glands of smokers, [28] which links it to decreased lung function and con rms FGFR1's role as a reliable marker in our analyses. The consistency of FGFR1's impact across different studies solidi es its status as a potential therapeutic target.…”

Capsaicin pretreatment attenuates salt-sensitive hypertension by alleviating AMPK/Akt/Nrf2 pathway in hypothalamic paraventricular nucleus

“…The PI3K/Akt signaling pathway is one of the most important intracellular signaling pathways in mammals, playing an important role in regulating various cellular functions, including metabolism, inflammation, oxidative stress, growth, and protein synthesis, but associated with diseases such as hypertension. Thus, the expression of key proteins in the PI3K/Akt pathway in spontaneously hypertensive rat PVN was significantly increased ( Shi et al, 2023 ), which promotes hypertension via sympathetic activation and vasopressin release. In the same hypertensive animal model, relaxin was shown to promote sympathetic nerve activation and blood pressure elevation from the PVN by stimulating PI3K expression and enhancing Akt phosphorylation However, PI3K inhibitor, LY294002, or Akt inhibitor (MK-2206) can eliminate the effects of relaxin on renal sympathetic nervous activity, mean arterial pressure, and plasma norepinephrine ( Bian et al, 2021 ).…”

Cullin 5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF

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