Alpha-lipoic acid regulates the autophagy of vascular smooth muscle cells in diabetes by elevating hydrogen sulfide level

Abstract

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.

Autophagy as a novel therapeutic target in vascular calcification

“…Recent studies have shown that autophagy induction inhibits both the endothelial dysfunction (Fetterman, et al, 2016;Y. Xie, et al, 2011) in endothelial cells from diabetic patients and phenotypic switching of VSMCs in diabetic vascular lesions (An, Li, Wei, Li, & Xu, 2018;Qiu, et al, 2018). These studies demonstrate a protective role of autophagy in diabetic vascular disorders.…”

α-Lipoic acid modulates liver fibrosis: A cross talk between TGF-β1, autophagy, and apoptosis

“…Such increment in autophagy expression is in harmony with Hernandez-Gea et al 9 who indicated that activation of HSCs triggers autophagy through providing the required energy resources for their activation, thus leading to the progression of liver fibrogenesis. Furthermore, we showed that the administration of ALA for 8 weeks counteracted this observed upregulated LC3-II expressed levels, which is in coherence with other studies that documented the blockade of autophagy in various cells after treatment with ALA. 21,42,43 Our data postulate that ALA modulates the progression of hepatic fibrosis via a possible correlation between autophagy suppression and inactivation of HSCs. Conversely, other studies showed that autophagic flux was enhanced during attenuation of hepatic fibrosis 44,45 through induction of HSC senescence.…”

Hydrogen sulfide and vascular regulation – An update

“… Action Mechanisms Cells/Models H 2 S gas/donor application (concentration) Refs. Promoting mitophagy Activation of Parkin recruited by PINK1 and then ubiquitination of Mfn2 RAECs NaHS (100 μM) [71] Inhibiting mitophagy Phosphorylation of Akt and dephosphorylation of FoxO3a MAECs NaHS (30 μM) [72] Inhibiting autophagy Dephosphorylation of AMPK and phosphorylation of mTOR VSMCs isolated from rat thoracic aorta NaHS (100 μM) [73] Inhibiting autophagy Dephosphorylation of AMPK and activation of Nrf2 RAECs/db/db mice NaHS (100 μM) [74] …”

“…However, several studies showed that both supplementation of H 2 S and the overexpression of its synthetases mitigated mitophagy [72] . H 2 S inhibited adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, which is closely associated with autophagy [73] . On the other hand, the ratio of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II to LC3-I is commonly used as an indicator of autophagy.…”