Salidroside improves endothelial function and alleviates atherosclerosis by activating a mitochondria-related AMPK/PI3K/Akt/eNOS pathway
Abstract
Salidroside (SAL) is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea. A recent study has reported that SAL can efficiently decrease atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice. This study was to investigate the molecular mechanism of antiatherogenic effects of SAL. Given the importance of endothelial nitric oxide synthase (eNOS) in atherosclerosis, we sought to elucidate whether SAL could stimulate eNOS activation and also to explore its upstream signaling pathway. Six-week old apoE(-/-) male mice were fed a high-fat diet for 8weeks and then were administered with SAL for another 8weeks. SAL significantly improved endothelial function associated with increasing eNOS activation, thus reduced the atherosclerotic lesion area. SAL increased eNOS-Ser1177 phosphorylation and decreased eNOS-Thr495 phosphorylation, indicative of eNOS activation in endothelium. The aortic sinus lesions in SAL treated mice displayed reduced inflammation. SAL significantly activated AMP-activated protein kinase (AMPK). Both AMPK inhibitor and AMPK small interfering RNA (siRNA) abolished SAL-induced Akt-Ser473 and eNOS-Ser1177 phosphorylation. In contrast, LY294002, the PI3k/Akt pathway inhibitor, abolished SAL-induced phosphorylation and expression of eNOS. High performance liquid chromatography (HPLC) analysis revealed that SAL decreased cellular ATP content and increased the cellular AMP/ATP ratio, which was associated with the activation of AMPK. SAL was found to decrease the mitochondrial membrane potential (ΔΨm), which is a likely consequence of reduced ATP production. The action of SAL to reduce atherosclerotic lesion formation may at least be attributed to its effect on improving endothelial function by promoting nitric oxide (NO) production, which was associated with mitochondrial depolarization and subsequent activation of the AMPK/PI3K/Akt/eNOS pathway. Taken together, our data described the effects of SAL on mitochondria, which played critical roles in improving endothelial function in atherosclerosis.
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The main mechanism of salidroside relied on stimulation of eNOS activation and NO production through AMPK-dependent activation of the phosphatidylinositol-3-kinase-protein kinase B pathway.
“The main mechanism relied on the stimulation of eNOS activation and NO production through the AMPK-dependent activation of the phosphatidylinositol-3-kinase- protein kinase B pathway [130].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [130]
Salidroside-induced AMPK activation was presumably related to moderate depolarization of ΔΨm and subsequent increase of the cytosolic AMP-to-ATP ratio.
“Salidroside-induced AMPK activation was presumably related to the moderate depolarization of ΔΨm and subsequent increase of the cytosolic AMP-to-ATP ratio [130].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [130]
Salidroside efficiently decreased atherosclerotic plaque formation in LDL receptor-deficient mice.
“Salidroside, a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea, efficiently decreased atherosclerotic plaque formation in LDL receptor-deficient mice [130].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [130]
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References 53 · Cited by 99
- Authors
- Xing, S.-S., Yang, X.-Y., Zheng, T., Li, W.-J., Wu, D., Chi, J.-Y., Bian, F., Bai, X.-L., Wu, G.-J., Zhang, Y.-Z., Zhang, C.-T., Zhang, Y.-H., Li, Y.-S., & Jin, S.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Corresponding author
- Jin, Si
- Venue
- Vascular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 72
- Pages
- 141-152
- ISSN
- 1537-1891 (ISSN-L)
- OpenAlex
- W911801646
- Cited by
- 99
- References
- 53
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 13 · 2020: 12 · 2019: 14 · 2018: 6 · 2017: 10 · 2016: 5 · 2015: 1
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Vascular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81070190, 81072634, 81373413, 81470458)
- Ministry of Education of the People's Republic of China (2013YGYL008, NCET-10-0409)
- National Major Science and Technology Projects of China (2011zx09102-004-001, 2013zx09103-001-020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Medicinal Plants and Bioactive Compounds
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ginseng Biological Effects and Applications
- Keywords
- salidroside, atherosclerosis, endothelial function, endothelial nitric oxide synthase, AMPK, PI3K/Akt signaling, mitochondrial depolarization, nitric oxide production, AMP/ATP ratio, ApoE-deficient mice, high-fat diet, antiatherogenic effects, Rhodiola rosea, mitochondrial membrane potential
- MeSH terms
- Adenosine Triphosphate, Animals, Glucosides, Male, Mitochondria, Nitric Oxide, Phenols, Phosphorylation, Signal Transduction, Rats, Wistar, Phosphatidylinositol 3-Kinases, Endothelial Cells, Atherosclerosis, Proto-Oncogene Proteins c-akt, Mice, Rats, Nitric Oxide Synthase Type III, AMP-Activated Protein Kinases, Diet, High-Fat
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