Department of Physiology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, China.
Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, China.
Biochim Biophys Acta Mol Basis Dis. 2018 Nov;1864(11):3723-3738. doi: 10.1016/j.bbadis.2018.09.005. Epub 2018 Sep 7.
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 (HS) level in diabetes and whether this effect is associated with regulation of autophagy of VSM cells (VSMCs). We found decreased serum HS levels in Chinese patients and rats with type 2 diabetes mellitus (T2DM). ALA treatment could increase HS 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-γ-lyase inhibitor, could weaken the ALA effect. In cultured VSMCs, high glucose level also reduced HS level, upregulated the autophagy-related index and activated the AMPK/mTOR pathway, which were reversed by concomitant application of sodium hydrosulfide (NaHS, an HS donor) or ALA. The protective effect of NaHS or ALA was attenuated by rapamycin (an autophagy activator), 5-amino-1-β-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 HS level and downregulating autophagy via the AMPK/mTOR pathway. This study provides a new target for addressing diabetic macroangiopathy.
功能失调的血管平滑肌（VSM）在 2 型糖尿病（T2DM）患者的动脉粥样硬化过程中起着至关重要的作用。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不清楚。本研究旨在确定 ALA 是否通过提高糖尿病患者的硫化氢（HS）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 2 型糖尿病患者和大鼠的血清 HS 水平降低。ALA 治疗可增加 HS 水平，降低自噬相关指标和 5'-单磷酸激活蛋白激酶（AMPK）/雷帕霉素靶蛋白（mTOR）通路的激活，从而保护 T2DM 大鼠的血管功能。丙炔甘氨酸（PPG），一种胱硫醚-γ-裂解酶抑制剂，可削弱 ALA 的作用。在培养的 VSMCs 中，高葡萄糖水平也降低了 HS 水平，上调了自噬相关指标并激活了 AMPK/mTOR 通路，这些作用可被同时应用的硫氢化钠（HS 的供体）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-羧酰胺（AMPK 激活剂）或 PPG 减弱。相反，化合物 C（AMPK 抑制剂）增强了 ALA 或 NaHS 的作用。ALA 通过升高 HS 水平并通过 AMPK/mTOR 通路下调自噬，可能对 T2DM 中的 VSMCs 具有保护作用。本研究为解决糖尿病大血管病变提供了一个新的靶点。
