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Alpha-Enolase Regulates the Malignant Phenotype of Pulmonary Artery Smooth Muscle Cells via the AMPK-Akt pathway

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posted on 07.11.2018, 00:00 authored by Jingbo Dai, Qiyuan Zhou, Jiwang Chen, Megan L. Rexius-Hall, Jalees Rehman, Guofei Zhou
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.

Funding

We would like to thank Ms. Rongzhen Zhou for her reading of our manuscript. The work is partly supported by NIH R01-HL123804 (G. Zhou), a National Natural Science Foundation of China (NSFC) grant 81770050 (G. Zhou), R01-GM094220 (J. Rehman), and P01-HL60678 (J. Rehman). The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We are thankful of Drs. Suzy A, A. Comhair and Serpil C. Erzurum at Department of Pathobiology, Respiratory Institute, Cleveland Clinic and the Pulmonary Hypertension Breakthrough Initiative (PHBI) to provide us with lung tissue sections from normal donors and PAH patients and human PASMC samples, respectively.

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Citation

Dai, J. B., Zhou, Q. Y., Chen, J. W., Rexius-Hall, M. L., Rehman, J., & Zhou, G. F. (2018). Alpha-enolase regulates the malignant phenotype of pulmonary artery smooth muscle cells via the AMPK-Akt pathway. Nature Communications, 9. doi:10.1038/s41467-018-06376-x

Publisher

Nature Research

Language

en_US

issn

2041-1723

Issue date

21/09/2018

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