Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension.
Akt-Dependent Glycolysis-Driven Lipogenesis Supports Proliferation and Survival of Human Pulmonary Arterial Smooth Muscle Cells in Pulmonary Hypertension.
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DOI：
10.3389/fmed.2022.886868
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发表时间：
2022
影响因子：
3.9
通讯作者：
Kudryashova, Tatiana V.
中科院分区：
文献类型：
--
作者：
Jiang, Lifeng;Goncharov, Dmitry A.;Shen, Yuanjun;Lin, Derek;Chang, Baojun;Pena, Andressa;DeLisser, Horace;Goncharova, Elena A.;Kudryashova, Tatiana V.
关键词：
肺动脉血管平滑肌细胞（PAVSMC）过度增殖是肺动脉高压（PAH）肺血管重构的重要病理组成部分。脂肪生成与许多增殖性疾病有关，但其在PAH中PAVSMC增殖中的作用仍有待阐明。我们发现，早代人PAH PAVSMC的关键脂肪酸合成酶ATP-柠檬酸裂解酶（ACLY），乙酰辅酶A羧化酶（ACC），脂肪酸合成酶（FATs）有显着的上调，并增加未受刺激的增殖相比，控制人PAVSMC。用变构ACC抑制剂5-十四烷氧基-2-糠酸（TOFA）治疗可显著降低人PAH PAVSMC的增殖并诱导凋亡。PAH PAVSMC的细胞内脂质含量和增殖并没有减少，但抑制了非代谢类似物的葡萄糖2-脱氧-D-葡萄糖（2-DG），并通过添加丙酮酸盐部分恢复孵育在脂质耗尽的媒体。蛋白激酶Akt在人PAH PAVSMC中以sirtuin 7（SIRT 7）和c-Jun N-末端激酶（JNK）依赖性方式上调。药理学抑制Akt可下调ACLY和ACC的表达，显著降低细胞内脂质含量，抑制人PAH PAVSMC的增殖并诱导其凋亡。总之，这些数据表明，人PAH PAVSMC具有上调的脂肪生成，其以Akt和糖酵解依赖性方式得到支持，并且是增加增殖和存活所需的。我们的数据表明糖酵解、脂肪生成和人PAH PAVSMC的增殖之间存在机制联系，并呼吁进一步研究以确定SIRT 7/JNK-Akt-脂肪生成轴作为抑制PAH中PAVSMC过度增殖的靶向途径的潜在吸引力。
Hyper-proliferation of pulmonary arterial vascular smooth muscle cells (PAVSMC) is an important pathological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Lipogenesis is linked to numerous proliferative diseases, but its role in PAVSMC proliferation in PAH remains to be elucidated. We found that early-passage human PAH PAVSMC had significant up-regulation of key fatty acids synthesis enzymes ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN), and increased unstimulated proliferation compared to control human PAVSMC. Treatment with an allosteric ACC inhibitor 5-tetradecyloxy-2-furoic acid (TOFA) significantly decreased proliferation and induced apoptosis of human PAH PAVSMC. Intracellular lipid content and proliferation of PAH PAVSMC were not reduced by incubation in lipid-depleted media but suppressed by a non-metabolizable analog of glucose 2-Deoxy-D-glucose (2-DG) and partially restored by addition of pyruvate. Protein kinase Akt was upregulated in human PAH PAVSMC in a sirtuin 7 (SIRT7)- and c-Jun N-terminal kinase (JNK)-dependent manner. Pharmacological inhibition of Akt down-regulated ACLY and ACC, significantly reduced intracellular lipid content, inhibited proliferation and induced apoptosis of human PAH PAVSMC. Taken together, these data demonstrate that human PAH PAVSMC have up-regulated lipogenesis, which is supported in an Akt- and glycolysis-dependent manner and is required for increased proliferation and survival. Our data suggest that there is a mechanistic link between glycolysis, lipogenesis, and the proliferation of human PAH PAVSMC and call for further studies to determine the potential attractiveness of a SIRT7/JNK-Akt-lipogenesis axis as a target pathway to inhibit PAVSMC hyper-proliferation in PAH.
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影响因子：
4
作者：
Baron, A;Migita, T;Loda, M
通讯作者：
Loda, M
影响因子：
3
作者：
Garat CV;Crossno JT Jr;Sullivan TM;Reusch JE;Klemm DJ
通讯作者：
Klemm DJ
影响因子：
4.3
作者：
Baenke F;Peck B;Miess H;Schulze A
通讯作者：
Schulze A
DOI：
10.1165/rcmb.2019-0226ps
发表时间：
2020-02-01
影响因子：
6.4
作者：
Hansmann, Georg;Calvier, Laurent;Chan, Stephen Y.
通讯作者：
Chan, Stephen Y.
DOI：
10.1016/j.bbrc.2018.11.120
发表时间：
2019-01-08
影响因子：
3.1
作者：
Kim, Ji-Hye;Kim, Dahee;Kim, Kwang Rol
通讯作者：
Kim, Kwang Rol