Alpha-enolase regulates the malignant phenotype of pulmonary artery smooth muscle cells via the AMPK-Akt pathway.
Alpha-enolase regulates the malignant phenotype of pulmonary artery smooth muscle cells via the AMPK-Akt pathway.
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DOI：
10.1038/s41467-018-06376-x
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发表时间：
2018-09-21
影响因子：
16.6
通讯作者：
Zhou G
中科院分区：
文献类型：
--
作者：
Dai J;Zhou Q;Chen J;Rexius-Hall ML;Rehman J;Zhou G
在肺动脉高压（PAH）发病过程中，在肺动脉平滑肌细胞（PASMC）中观察到的代谢向糖酵解增加转变的分子机制尚未完全了解。在这里，我们表明，糖酵解酶α-烯醇化酶（ENO 1）调节PASMC的代谢重编程和恶性表型。我们发现，在PAH相关患者和缺氧性肺动脉高压（HPH）动物模型中，ENO 1水平升高。EN 01的沉默或抑制降低PASMC增殖和去分化，并诱导PASMC凋亡，而EN 01的过表达通过AMPK-Akt途径促进合成的、去分化的和抗肿瘤的表型。抑制ENO 1可防止PASMC中缺氧诱导的从线粒体呼吸到糖酵解的代谢转变。最后，我们发现，药理学抑制ENO 1逆转HPH在小鼠和大鼠，表明ENO 1作为一种调节剂的致病代谢重编程HPH。平滑肌细胞（SMC）的代谢重编程在肺动脉高压（PAH）的发病机制中起着重要作用。在此，Dai等人表明糖酵解酶α-烯醇化酶有助于这种重编程，并且其抑制限制了PAH动物模型中SMC增殖和疾病进展。
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. Metabolic reprogramming of smooth muscle cells (SMCs) plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Here, Dai et al. show that the glycolytic enzyme alpha-enolase contributes to this reprogramming, and that its inhibition limits SMC proliferation and disease progression in animal models of PAH.
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影响因子：
37.8
作者：
Caruso P;Dunmore BJ;Schlosser K;Schoors S;Dos Santos C;Perez-Iratxeta C;Lavoie JR;Zhang H;Long L;Flockton AR;Frid MG;Upton PD;D'Alessandro A;Hadinnapola C;Kiskin FN;Taha M;Hurst LA;Ormiston ML;Hata A;Stenmark KR;Carmeliet P;Stewart DJ;Morrell NW
通讯作者：
Morrell NW
影响因子：
37.8
作者：
Lai YC;Tabima DM;Dube JJ;Hughan KS;Vanderpool RR;Goncharov DA;St Croix CM;Garcia-Ocaña A;Goncharova EA;Tofovic SP;Mora AL;Gladwin MT
通讯作者：
Gladwin MT
影响因子：
7.3
作者：
Agard, C.;Rolli-Derkinderen, M.;Pacaud, P.
通讯作者：
Pacaud, P.
影响因子：
37.8
作者：
Goncharov DA;Kudryashova TV;Ziai H;Ihida-Stansbury K;DeLisser H;Krymskaya VP;Tuder RM;Kawut SM;Goncharova EA
通讯作者：
Goncharova EA
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.