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Subendothelial retention of apolipoprotein B100-containing lipoprotein, such as low-density lipoprotein (LDL), is the initial step of atherogenesis. Activation of autophagy exhibits beneficial effects for the treatment of atherosclerosis. In our previous study, we demonstrated that hyperglycemia suppressed autophagic degradation of caveolin-1, which in turn resulted in acceleration of caveolae-mediated LDL transcytosis across endothelial cells and lipid retention. Therefore, targeting the crossed pathway in autophagy activation and LDL transcytosis interruption may be a promising antiatherosclerotic strategy. In metabolic diseases, including atherosclerosis, salidroside, a phenylpropanoid glycoside compound (3,5-dimethoxyphenyl) methyl- β -glucopyranoside), is the most important compound responsible for the therapeutic activities of Rhodiola . However, whether salidroside suppresses LDL transcytosis to alleviate atherosclerosis has not yet been elucidated. In the present study, we demonstrated that salidroside significantly decreased LDL transcytosis across endothelial cells. Salidroside-induced effects were dramatically blocked by AMPK (adenosine monophosphate-activated protein kinase) inhibitor (compound c, AMPKα siRNA) and by overexpression of exogenous tyrosine-phosphorylated caveolin-1 using transfected cells with phosphomimicking caveolin-1 on tyrosine 14 mutant plasmids (Y14D). Furthermore, we observed that salidroside promoted autophagosome formation via activating AMPK. Meanwhile, the interaction between caveolin-1 and LC3B-II, as well as the interaction between active Src (indicated by the phosphorylation of Src on tyrosine 416) and LC3B-II, was significantly increased, upon stimulation with salidroside. In addition, both bafilomycin A 1 (a lysosome inhibitor) and an AMPK inhibitor (compound c) markedly prevented salidroside-induced autophagic degradation of p-Src and caveolin-1. Moreover, the phosphorylation of caveolin-1 on tyrosine 14 was disrupted due to the downregulation of p-Src and caveolin-1, thereby directly decreasing LDL transcytosis by attenuating the number of caveolae on the cell membrane and by preventing caveolae-mediated LDL endocytosis released from the cell membrane. In ApoE -/- mice, salidroside significantly delayed the formation of atherosclerotic lesions. Meanwhile, a significant increase in LC3B, accompanied by attenuated accumulation of the autophagy substrate SQSTM1, was observed in aortic endothelium of ApoE -/- mice. Taken together, our findings demonstrated that salidroside protected against atherosclerosis by inhibiting LDL transcytosis through enhancing the autophagic degradation of active Src and caveolin-1., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Xiangli Bai et al.)

Salidroside (SAL) is a phenylethanoid glycoside isolated from the medicinal plant Rhodiola rosea. R. rosea has been reported to have beneficial effects on diabetic nephropathy (DN) and high-glucose (HG)-induced mesangial cell proliferation. Given the importance of caveolin-1 (Cav-1) in transcytosis of albumin across the endothelial barrier, the present study was designed to elucidate whether SAL could inhibit Cav-1 phosphorylation and reduce the albumin transcytosis across glomerular endothelial cells (GECs) to alleviate diabetic albuminuria as well as to explore its upstream signaling pathway. To assess the therapeutic potential of SAL and the mechanisms involved in DN albuminuria, we orally administered SAL to db/db mice, and the effect of SAL on the albuminuria was measured. The albumin transcytosis across GECs was explored in a newly established in vitro cellular model. The ratio of albumin to creatinine was significantly reduced upon SAL treatment in db/db mice. SAL decreased the albumin transcytosis across GECs in both normoglycemic and hyperglycemic conditions. SAL reversed the HG-induced downregulation of AMP-activated protein kinase and upregulation of Src kinase and blocked the upregulation Cav-1 phosphorylation. Meanwhile, SAL decreased mitochondrial superoxide anion production and moderately depolarized mitochondrial membrane potential. We conclude that SAL exerts its proteinuria-alleviating effects by downregulation of Cav-1 phosphorylation and inhibition of albumin transcytosis across GECs. These studies provide the first evidence of interference with albumin transcytosis across GECs as a novel approach to the treatment of diabetic albuminuria., (Copyright © 2016 the American Physiological Society.)

Background and Purpose: Recent reports have suggested that salidroside could protect cardiomyocytes from oxidative injury and stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). The aim of this study was to evaluate the therapeutic effects of salidroside on diabetic mice and to explore the underlying mechanisms., Experimental Approach: The therapeutic effects of salidroside on type 2 diabetes were investigated. Increasing doses of salidroside (25, 50 and 100 mg·kg(-1) ·day(-1)) were administered p.o. to db/db mice for 8 weeks. Biochemical analysis and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. Primary cultured mouse hepatocytes were used to further explore the underlying mechanisms in vitro., Key Results: Salidroside dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Hypolipidaemic effects and amelioration of liver steatosis were observed after salidroside administration. In vitro, salidroside dose-dependently induced an increase in the phosphorylations of AMPK and PI3K/Akt, as well as glycogen synthase kinase 3β (GSK3β) in hepatocytes. Furthermore, salidroside-stimulated AMPK activation was found to suppress the expression of PEPCK and glucose-6-phosphatase. Salidroside-induced AMPK activation also resulted in phosphorylation of acetyl CoA carboxylase, which can reduce lipid accumulation in peripheral tissues. In isolated mitochondria, salidroside inhibited respiratory chain complex I and disturbed oxidation/phosphorylation coupling and moderately depolarized the mitochondrial membrane potential, resulting in a transient increase in the AMP/ATP ratio., Conclusions and Implications: Salidroside exerts an antidiabetic effect by improving the cellular metabolic flux through the activation of a mitochondria-related AMPK/PI3K/Akt/GSK3β pathway., (© 2015 The British Pharmacological Society.)