Volume 72, September 2015, Pages 141–152
- a Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- b The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China
- c Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China
- Received 15 December 2014, Revised 17 June 2015, Accepted 11 July 2015, Available online 15 July 2015
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 8 weeks and then were
administered with SAL for another 8 weeks. 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.
Graphical abstract
Abbreviations
- ACh, acetylcholine;
- Akt, protein kinase B;
- AMPKα, AMP-activated protein kinase α;
- BW, body weight;
- DAF-FM-DA, 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate;
- DHE, dihydroethidium;
- EDR, endothelium-dependent relaxations;
- eNOS, endothelial nitric oxide synthase;
- FBG, fasting blood glucose;
- JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolyl-carbocyanine iodide;
- HDL-c, HDL cholesterol;
- HFD, high fat diet;
- HPLC, high-performance liquid chromatography;
- LDL-c, LDL cholesterol;
- l-NAME, NG-nitro-l-arginine methyl ester;
- PE, phenylephrine;
- SAL, salidroside;
- SBP, systolic blood pressure;
- TC, total cholesterol;
- TG, triglyceride;
- ΔΨm, mitochondrial membrane potential
Keywords
- Atherosclerosis;
- Endothelial dysfunction;
- Salidroside;
- Mitochondria
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