Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis

Abstract

Vascular endothelial cells are highly sensitive to oxidative stress, and this is one of the mechanisms by which widespread endothelial dysfunction is induced in most cardiovascular diseases and disorders. However, how these cells can survive in oxidative stress environments remains unclear. Salidroside, a traditional Chinese medicine, has been shown to confer vascular protective effects. We aimed to understand the role of autophagy and its regulatory mechanisms by treating human umbilical vein endothelial cells (HUVECs) with salidroside under oxidative stress. HUVECs were treated with salidroside and exposed to hydrogen peroxide (HO). The results indicated that salidroside exerted cytoprotective effects in an HO-induced HUVEC injury model and suppressed HO-induced apoptosis of HUVECs. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased oxidative stress-induced HUVEC apoptosis, while the autophagy activator rapamycin induced anti-apoptosis effects in HUVECs. Salidroside increased autophagy and decreased apoptosis of HUVECs in a dose-dependent manner under oxidative stress. Moreover, 3-MA attenuated salidroside-induced HUVEC autophagy and promoted apoptosis, whereas rapamycin had no additional effects compared with salidroside alone. Salidroside upregulated AMPK phosphorylation but downregulated mTOR phosphorylation under oxidative stress; however, administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with salidroside alone. These results suggest that autophagy is a protective mechanism in HUVECs under oxidative stress and that salidroside might promote autophagy through activation of the AMPK pathway and downregulation of mTOR pathway.

Antagonistic effects of selenium on lead-induced autophagy by influencing mitochondrial dynamics in the spleen of chickens

“…This result suggests that Pb can not enhance the apoptosis in the spleen of chickens. Notably, other reports indicated that oxidative stress was closely associated with autophagy [38, 39]. In H9c2 rat cardiomyoblasts, oxidative stress may suppress mTOR activity and promote autophagy [40].…”

Rhodiola rosea L.: an Herb with Anti-Stress, Anti-Aging, and Immunostimulating Properties for Cancer Chemoprevention

“…In addition, salidroside was shown to promote angiogenic differentiation of human bone marrow-derived endothelial progenitor cells [105] and to protect against oxidative endothelial injury by activation of the mTOR pathway [105–107]. Salidroside also inhibited CT-26 and Lewis lung carcinoma tumor-induced cachexia and the loss of tumor-free body weight, adipose and gastrocnemius muscles, as well as extended the survival of the treated mice by increasing the expression of phosphorylated mTOR both in C2C12 myotubes and in gastrocnemius muscle of the mice [108].…”

mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging

“…Additionally, the central role of oxidative stress in age‐related cerebrovascular dysfunction (Sure et al, ) was recently demonstrated in studies showing that the age‐related deterioration of cerebrovascular endothelial cell function and neurovascular coupling responses were reversed by reducing oxidative stress in endothelial cells (Kiss et al, ; Tarantini et al, , ). Inhibition of mTOR is protective against oxidative stress in vitro in vascular endothelial cells (Zheng et al, ), indicating that mTOR may also regulate oxidative stress. While we have not addressed the role of mTOR‐driven neuroinflammation or oxidative stress in our studies, these may represent important mechanisms through which mTOR inhibition ameliorates cerebrovascular dysfunction and cognitive impairment in the aging brain.…”