Alpha-lipoic acid regulates the autophagy of vascular smooth muscle cells in diabetes by elevating hydrogen sulfide level
Alpha-lipoic acid regulates the autophagy of vascular smooth muscle cells in diabetes by elevating hydrogen sulfide level
复制标题
α-硫辛酸通过提高硫化氢水平来调节糖尿病血管平滑肌细胞的自噬。
DOI：
10.1016/j.bbadis.2018.09.005
复制
发表时间：
2018-11-01
影响因子：
6.2
通讯作者：
Wu, Yuming
中科院分区：
文献类型：
--
作者：
Qiu, Xuan;Liu, Kuanzhi;Wu, Yuming
2型糖尿病（T2 DM）患者的血管平滑肌功能异常（VSM）在动脉粥样硬化的发生发展过程中起着重要作用。α-硫辛酸（ALA）可预防糖尿病引起的VSM改变。然而，ALA有益作用的确切机制尚未完全了解。本研究旨在确定ALA是否通过升高糖尿病患者的硫化氢（H2S）水平来改善VSM功能，以及这种作用是否与VSM细胞（VSMCs）自噬的调节有关。我们发现中国人和2型糖尿病（T2 DM）大鼠血清H2S水平降低。ALA治疗可提高H2S水平，降低自噬相关指数，降低5 '-单磷酸活化蛋白激酶（AMPK）/哺乳动物雷帕霉素靶蛋白（mTOR）通路的激活，从而保护T2 DM大鼠血管功能。胱硫醚-γ-裂解酶抑制剂炔丙基甘氨酸（PPG）可减弱ALA的作用。在培养的VSMCs中，高糖水平也降低了H2S水平，上调了自噬相关指数，激活了AMPK/mTOR通路，这些都被同时应用硫氢化钠（NaHS，H2S供体）或ALA逆转。NaHS或ALA的保护作用被雷帕霉素（自噬激活剂）、5-氨基-1-β-d-呋喃核糖基-咪唑-4-甲酰胺（AMPK激活剂）或PPG减弱。相反，化合物C（AMPK抑制剂）增强ALA或NaHS的作用。ALA可能通过升高H2S水平，下调AMPK/mTOR通路的自噬作用，对T2 DM时VSMCs具有保护作用。本研究为解决糖尿病大血管病变提供了新的靶点。
Dysfunctional vascular smooth muscle (VSM) plays a vital role in the process of atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Alpha-lipoic acid (ALA) can prevent the altered VSM induced by diabetes. However, the precise mechanism underlying the beneficial effect of ALA is not well understood. This study aimed to determine whether ALA ameliorates VSM function by elevating hydrogen sulfide (H2S) level in diabetes and whether this effect is associated with regulation of autophagy of VSM cells (VSMCs). We found decreased serum H2S levels in Chinese patients and rats with type 2 diabetes mellitus (T2DM). ALA treatment could increase H2S level, which reduced the autophagy-related index and activation of the 5'-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, thereby protecting vascular function in rats with T2DM. Propargylglycine (PPG), a cystathionine-gamma-lyase inhibitor, could weaken the ALA effect. In cultured VSMCs, high glucose level also reduced H2S level, upregulated the autophagy-related index and activated the AMPK/mTOR pathway, which were reversed by concomitant application of sodium hydrosulfide (NaHS, an H2S donor) or ALA. The protective effect of NaHS or ALA was attenuated by rapamycin (an autophagy activator), 5-amino-1-beta-d-ribofuranosyl-imidazole-4-carboxamide (an AMPK activator) or PPG. In contrast, Compound C (an AMPK inhibitor) enhanced the effect of ALA or NaHS. ALA may have a protective effect on VSMCs in T2DM by elevating H2S level and downregulating autophagy via the AMPK/mTOR pathway. This study provides a new target for addressing diabetic macroangiopathy.