Salidroside attenuates hypoxia/reoxygenation‑induced human brain vascular smooth muscle cell injury by activating the SIRT1/FOXO3α pathway

Abstract

It has been reported that salidroside (SAL), a natural dietary isothiocyanate, exhibits neuroprotective roles in cerebral ischemia-reperfusion injury. However, to the best of our knowledge, its underlying protective mechanism remains unknown. Sirtuin 1 (SIRT1) is a class III histone deacetylase involved in a variety of cellular functions. SIRT1 has been identified as a mediator of cerebral ischemia and may induce neuroprotection by activating various intracellular downstream targets, such as forkhead box protein O3α (FOXO3α). Therefore, the present study aimed to investigate whether SAL protects human brain vascular smooth muscle cells (HBVSMC) against hypoxia/reoxygenation (H/R) injury, which is a cell model of cerebral ischemia-reperfusion injury, through regulating the SIRT1-activited signaling pathway. The present study revealed that H/R treatment significantly reduced the expression of SIRT1 protein in HBVSMCs. Additionally, pretreatment with SAL reversed the H/R-induced decrease in cellular viability, increased caspase-3 activity, the appearance of apoptotic cells and the apoptosis rate in HBVSMCs. SAL attenuated the H/R-induced decrease in the expression of SIRT1 and phosphorylated FOXO3α protein in HBVSMCs, suggesting that the protective role of SAL in H/R injury occurs via the SIRT1/FOXO3α pathway. Furthermore, sirtinol, a SIRT1-specific inhibitor, suppressed the inhibitory effects of SAL on H/R-induced cytotoxicity and apoptosis as indicated by the downregulation of cell viability and upregulation of caspase-3 activity and apoptosis rate induced by sirtinol treatment in HBVSMCs. The reversal effects of SAL on H/R-induced alternation of B-cell lymphoma (Bcl-2) and Bcl-2 associated X protein expression were also attenuated by sirtinol. These results suggest that SAL exhibits neuroprotective effects against H/R injury by activating the SIRT1/FOXO3α pathway, which may become a novel potential therapeutic target for the treatment of cerebral ischemic disease.

MiR‐629 regulates hypoxic pulmonary vascular remodelling by targeting FOXO3 and PERP

“…Studies demonstrated that FOXO3 functionally interacted with the PI3K/AKT signalling pathway to regulate the proliferation of smooth muscle cells . In addition, activation of FOXO3 contribute to the protective effects of salidroside on hypoxia/reoxygenation‐induced human brain vascular smooth muscle cell injury . FOXO3 was down‐regulated in the fibroblasts isolated from PAH calves and patients with idiopathic PAH and functioned as an important mediator in the miR‐124‐mediated proliferation of pulmonary vascular fibroblasts, suggesting the potential role of FOXO3 in the pathophysiology of PAH.…”

Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

“…Moreover, resveratrol modulates the activity of SIRT3 and SIRT5 ( Dai et al, 2018 ). Several other natural extracts also activate SIRT1, including magnolol ( Kou et al, 2017 ), oxymatrine ( Zhou et al, 2018 ), curcumin ( Miao et al, 2016 ), salvianolic acid B ( Lv et al, 2015 ), arctigenin ( Zhang S. et al, 2017 ), astaxanthin ( Zhang et al, 2019 ), salidroside ( Xu et al, 2018 ), ginsenoside ( Cheng et al, 2019 ), icariin ( Zhu et al, 2010 ), low molecular weight fucoidan ( Wang et al, 2016 ), and saponin from Aralia taibaiensis ( Duan et al, 2019 ). These findings suggest that Chinese traditional medicine may be a source of sirtuin modulators.…”

Salidroside Ameliorates Cardiomyocyte Hypertrophy by Upregulating Peroxisome Proliferator-Activated Receptor-α

“…Therefore, salidroside elevates ATGL expression and then generates more ligands for PPARα to inhibit cardiac hypertrophy. Salidroside can affect the function of some protein factors such as sirt1, FOXOs and AMPK ( Lan et al, 2017 ; Xu et al, 2018 ; Li et al, 2019 ). Salidroside elevated the protein expressions of SIRT1 and phosphorylated FOXO3α and then attenuated the injury of human brain vascular smooth muscle cells induced by the hypoxia/reoxygenation treatment ( Xu et al, 2018 ).…”

“…Salidroside can affect the function of some protein factors such as sirt1, FOXOs and AMPK ( Lan et al, 2017 ; Xu et al, 2018 ; Li et al, 2019 ). Salidroside elevated the protein expressions of SIRT1 and phosphorylated FOXO3α and then attenuated the injury of human brain vascular smooth muscle cells induced by the hypoxia/reoxygenation treatment ( Xu et al, 2018 ). In colitis mice, the expressions of SIRT1, FOXO1, FOXO3α, and FOXO4 could be increased by salidroside to attenuate inflammation reaction ( Li et al, 2019 ).…”