Sirtuin 3 governs autophagy-dependent glycolysis during Angiotensin II-induced endothelial-to-mesenchymal transition
Sirtuin 3 governs autophagy-dependent glycolysis during Angiotensin II-induced endothelial-to-mesenchymal transition
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DOI：
10.1096/fj.202001494r
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发表时间：
2020-11-01
期刊：
影响因子：
4.8
通讯作者：
Shen, Weili
中科院分区：
文献类型：
--
作者：
Gao, Jing;Wei, Tong;Shen, Weili
自噬受损会导致参与内皮间质转化 (EndoMT) 的细胞代谢扰动。然而，细胞自噬机制和内皮代谢之间的相互作用仍然难以捉摸。 Sirtuin 3 (SIRT3) 是一种 NAD 依赖性脱乙酰酶，是能量代谢的主要细胞传感器。这项工作的目的是确定 SIRT3 介导的自噬在细胞代谢和 EndoMT 过程中的作用。我们证明，血管紧张素 II (Ang II) 会导致内皮细胞 (EC) 中自噬流缺陷和高水平糖酵解，并伴有 EndoMT 期间线粒体 SIRT3 的丢失。 SIRT3 的缺失进一步诱导内源性自噬调节基因 5 (ATG5) 的过度乙酰化，进而抑制自噬体成熟并增加丙酮酸激酶 M2 (PKM2) 二聚体的表达。 M2 二聚体是 PKM2 活性较低的形式，可通过有氧糖酵解驱动葡萄糖。此外，TEPP-46（一种选择性 PKM2 四聚体激活剂）可产生较低浓度的乳酸，并导致体外和体内 EndoMT 减少。与此同时，阻断乳酸从 EC 流入血管平滑肌细胞 (VSMC) 会下调合成 VSMC 标记物。 EC特异性SIRT3转基因小鼠表现出内皮细胞转化减少，但血管纤维化和胶原蛋白积累得到部分挽救。综上所述，这些发现表明 SIRT3 通过改善 PKM2 的自噬降解来调节 EndoMT。因此，糖酵解代谢的药理学靶向可能代表高血压血管重塑的有效治疗策略。
The impairment of autophagy can cause cellular metabolic perturbations involved in endothelial-to-mesenchymal transition (EndoMT). However, the interplay between the cellular autophagy machinery and endothelial metabolism remains elusive. Sirtuin 3 (SIRT3), an NAD-dependent deacetylase, is a major cellular sensor of energy metabolism. The aim of this work was to determine the role of SIRT3-mediated autophagy in cellular metabolism and the process of EndoMT. We demonstrated that Angiotensin II (Ang II) led to defective autophagic flux and high levels of glycolysis in endothelial cells (ECs) accompanied by a loss of mitochondrial SIRT3 during EndoMT. The loss of SIRT3 further induced the hyperacetylation of endogenous autophagy-regulated gene 5 (ATG5), which in turn inhibited autophagosome maturation and increased pyruvate kinase M2 (PKM2) dimer expression. The M2 dimer is the less active form of PKM2, which drives glucose through aerobic glycolysis. Additionally, TEPP-46, a selective PKM2 tetramer activator, produced lower concentrations of lactate and led to the reduction of EndoMT both in vitro and in vivo. In parallel, the blockade of lactate influx from ECs into vascular smooth muscle cells (VSMCs) downregulated synthetic VSMC markers. EC-specific SIRT3 transgenic mice exhibited reduced endothelial cell transition but partial rescue of vascular fibrosis and collagen accumulation. Taken together, these findings reveal that SIRT3 regulates EndoMT by improving the autophagic degradation of PKM2. Pharmacological targeting of glycolysis metabolism may, therefore, represent an effective therapeutic strategy for hypertensive vascular remodeling.