Open Access

Salidroside attenuates oxidized low‑density lipoprotein‑induced endothelial cell injury via promotion of the AMPK/SIRT1 pathway

  • Authors:
    • Dongming Zhao
    • Xinyi Sun
    • Shujie Lv
    • Miying Sun
    • Huatao Guo
    • Yujia Zhai
    • Zhi Wang
    • Peng Dai
    • Lina Zheng
    • Mingzhe Ye
    • Xinpeng Wang
  • View Affiliations

  • Published online on: April 1, 2019     https://doi.org/10.3892/ijmm.2019.4153
  • Pages: 2279-2290
  • Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Oxidized low‑density lipoprotein (ox‑LDL)‑induced endothelial damage contributes to the initiation and pathogenesis of atherosclerosis. Salidroside can alleviate atherosclerosis and attenuate endothelial cell injury induced by ox‑LDL. However, the mechanisms involved in this process are not fully understood. Therefore, the purpose of the present study was to investigate the role of the adenosine monophosphate‑activated protein kinase (AMPK)/sirtuin (SIRT)1 pathway in the protection of salidroside against ox‑LDL‑induced human umbilical vein endothelial cells (HUVECs) injuries. The results revealed that salidroside reverses ox‑LDL‑induced HUVECs injury as demonstrated by the upregulation of cell viability and downregulation of LDH release. In addition, salidroside increased the expression of the SIRT1 protein in ox‑LDL‑treated HUVECs. Next, it was demonstrated that SIRT1 knockdown induced by transfection with small interfering (si)RNA targeting SIRT1 (siSRT1) abolished the protection of salidroside against ox‑LDL‑induced HUVECs injuries. This was illustrated by a decrease in cell viability and an increase in LDH release, caspase‑3 activity and apoptosis rate. Furthermore, salidroside mitigated ox‑LDL‑induced reactive oxygen species production, upregulated malondialdehyde content and NADPH oxidase 2 expression and decreased superoxide dismutase and glutathione peroxidase activities, while these effects were also reversed by siSIRT1 transfection. In addition, it was demonstrated that salidroside suppressed ox‑LDL‑induced mitochondrial dysfunction as demonstrated by the increase in mitochondrial membrane potential and decreases in cytochrome c expression, and Bax/Bcl‑2 reductions. However, these effects were eliminated by SIRT1 knockdown. Finally, it was demonstrated that salidroside significantly upregulated the phosphorylated‑AMPK expression in ox‑LDL‑treated HUVECs and AMPK knockdown induced by transfection with AMPK siRNA (siAMPK) leads to elimination of the salidroside‑induced increase in cell viability and the decrease in LDH release. Notably, siAMPK transfection further decreased the expression of SIRT1. In conclusion, these results suggested that salidroside protects HUVECs against ox‑LDL injury through inhibiting oxidative stress and improving mitochondrial dysfunction, which were dependent on activating the AMPK/SIRT1 pathway.

References

1 

Libby P, Ridker PM and Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature. 473:317–325. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Gao S and Liu J: Association between circulating oxidized low-density lipoprotein and atherosclerotic cardiovascular disease. Chronic Dis Transl Med. 3:89–94. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Pirillo A, Norata GD and Catapano AL: LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm. 2013:1527862013. View Article : Google Scholar : PubMed/NCBI

4 

Pahwa R and Jialal I: Atherosclerosis. StatPearls Publishing Treasure; Island, FL: 2019

5 

Taniyama Y and Griendling KK: Reactive oxygen species in the vasculature: Molecular and cellular mechanisms. Hypertension. 42:1075–1081. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Sorescu D and Griendling KK: Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail. 8:132–140. 2002. View Article : Google Scholar : PubMed/NCBI

7 

Madamanchi NR and Runge MS: Mitochondrial dysfunction in atherosclerosis. Circ Res. 100:460–473. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Panth N, Paudel KR and Parajuli K: Reactive oxygen species: A key hallmark of cardiovascular disease. Adv Med. 2016:91527322016. View Article : Google Scholar : PubMed/NCBI

9 

Victor VM, Apostolova N, Herance R, Hernandez-Mijares A and Rocha M: Oxidative stress and mitochondrial dysfunction in atherosclerosis: Mitochondria-targeted antioxidants as potential therapy. Curr Med Chem. 16:4654–4667. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Lum H and Roebuck KA: Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol. 280:C719–C741. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Sun P, Song SZ, Jiang S, Li X, Yao YL, Wu YL, Lian LH and Nan JX: Salidroside regulates inflammatory response in raw 264.7 macrophages via TLR4/TAK1 and ameliorates inflammation in alcohol binge drinking-induced liver injury. Molecules. 21:E14902016. View Article : Google Scholar : PubMed/NCBI

12 

Ni J, Li Y, Li W and Guo R: Salidroside protects against foam cell formation and apoptosis, possibly via the MAPK and AKT signaling pathways. Lipids Health Dis. 16:1982017. View Article : Google Scholar : PubMed/NCBI

13 

Ju L, Wen X, Wang C, Wei Y, Peng Y, Ding Y, Feng L and Shu L: Salidroside, a natural antioxidant, improves β-cell survival and function via activating AMPK pathway. Frontiers Pharmacol. 8:7492017. View Article : Google Scholar

14 

Zhang P, Li Y, Guo R and Zang W: Salidroside protects against advanced glycation end products-induced vascular endothelial dysfunction. Med Sci Monit. 24:2420–2428. 2018. View Article : Google Scholar : PubMed/NCBI

15 

Xing SS, Yang XY, Zheng T, Li WJ, Wu D, Chi JY, Bian F, Bai XL, Wu GJ, Zhang YZ, et al: Salidroside improves endo-thelial function and alleviates atherosclerosis by activating a mitochondria-related AMPK/PI3K/Akt/eNOS pathway. Vascul Pharmacol. 72:141–152. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Panossian A, Hamm R, Wikman G and Efferth T: Mechanism of action of Rhodiola, salidroside, tyrosol and triandrin in isolated neuroglial cells: An interactive pathway analysis of the downstream effects using RNA microarray data. Phytomedicine. 21:1325–1348. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Xing SS, Li J, Chen L, Yang YF, He PL, Li J and Yang J: Salidroside attenuates endothelial cellular senescence via decreasing the expression of inflammatory cytokines and increasing the expression of SIRT3. Mech Ageing Dev. 175:1–6. 2018. View Article : Google Scholar : PubMed/NCBI

18 

Kitada M, Ogura Y and Koya D: The protective role of Sirt1 in vascular tissue: Its relationship to vascular aging and atherosclerosis. Aging. 8:2290–2307. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Winnik S, Auwerx J, Sinclair DA and Matter CM: Protective effects of sirtuins in cardiovascular diseases: From bench to bedside. Eur Heart J. 36:3404–3412. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Ma L and Li Y: SIRT1: Role in cardiovascular biology. Clin Chim Acta. 440:8–15. 2015. View Article : Google Scholar

21 

Chong ZZ, Shang YC, Wang S and Maiese K: SIRT1: New avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets. 16:167–178. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Ota H, Eto M, Ogawa S, Iijima K, Akishita M and Ouchi Y: SIRT1/eNOS axis as a potential target against vascular senescence, dysfunction and atherosclerosis. J Atheroscler Thromb. 17:431–435. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Yang L, Cong HL, Wang SF and Liu T: AMP-activated protein kinase mediates the effects of lipoprotein-associated phospholipase A2 on endothelial dysfunction in atherosclerosis. Exp Ther Med. 13:1622–1629. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Wang S, Song P and Zou MH: AMP-activated protein kinase, stress responses and cardiovascular diseases. Clin Sci. 122:555–573. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR and Auwerx J: Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11:213–219. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Stein S and Matter CM: Protective roles of SIRT1 in atherosclerosis. Cell Cycle. 10:640–647. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Martin-Ventura JL, Rodrigues-Diez R, Martinez-Lopez D, Salaices M, Blanco-Colio LM and Briones AM: Oxidative stress in human atherothrombosis: Sources, markers and therapeutic targets. Int J Mol Sci. 18:E23152017. View Article : Google Scholar : PubMed/NCBI

28 

Georgieva E, Ivanova D, Zhelev Z, Bakalova R, Gulubova M and Aoki I: Mitochondrial dysfunction and redox imbalance as a diagnostic marker of 'Free Radical Diseases'. Anticancer Res. 37:5373–5381. 2017.PubMed/NCBI

29 

Vásquez-Trincado C, García-Carvajal I, Pennanen C, Parra V, Hill JA, Rothermel BA and Lavandero S: Mitochondrial dynamics, mitophagy and cardiovascular disease. J Physiol. 594:509–525. 2016. View Article : Google Scholar

30 

Salminen A, Kaarniranta K and Kauppinen A: Age-related changes in AMPK activation: Role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res Rev. 28:15–26. 2016. View Article : Google Scholar : PubMed/NCBI

31 

Mudau M, Genis A, Lochner A and Strijdom H: Endothelial dysfunction: The early predictor of atherosclerosis. Cardiovasc J Afr. 23:222–231. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Zou H, Liu X, Han T, Hu D, Wang Y, Yuan Y, Gu J, Bian J, Zhu J and Liu ZP: Salidroside protects against cadmium-induced hepatotoxicity in rats via GJIC and MAPK pathways. PLoS One. 10:e01297882015. View Article : Google Scholar : PubMed/NCBI

33 

Zhu Y, Shi YP, Wu D, Ji YJ, Wang X, Chen HL, Wu SS, Huang DJ and Jiang W: Salidroside protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via PI3K-Akt dependent pathway. DNA Cell Biol. 30:809–819. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Tan CB, Gao M, Xu WR, Yang XY, Zhu XM and Du GH: Protective effects of salidroside on endothelial cell apoptosis induced by cobalt chloride. Biol Pharm Bull. 32:1359–1363. 2009. View Article : Google Scholar : PubMed/NCBI

35 

Wu YL, Piao DM, Han XH and Nan JX: Protective effects of salidroside against acetaminophen-induced toxicity in mice. Biol Pharm Bull. 31:1523–1529. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Sun L, Dou F, Chen J, Chi H, Xing S, Liu T, Sun S and Chen C: Salidroside slows the progression of EA.hy926 cell senescence by regulating the cell cycle in an atherosclerosis model. Mol Med Rep. 17:257–263. 2018.

37 

Wang CY, Sun ZN, Wang MX and Zhang C: SIRT1 mediates salidroside-elicited protective effects against MPP+-induced apoptosis and oxidative stress in SH-SY5Y cells: Involvement in suppressing MAPK pathways. Cell Biol Int. 42:84–94. 2018. View Article : Google Scholar

38 

Wang Y, Xu CF, Liu YJ, Mao YF, Lv Z, Li SY, Zhu XY and Jiang L: Salidroside attenuates ventilation induced lung injury via SIRT1-dependent inhibition of NLRP3 inflammasome. Cell Physiol Biochem. 42:34–43. 2017. View Article : Google Scholar : PubMed/NCBI

39 

Si PP, Zhen JL, Cai YL, Wang WJ and Wang WP: Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress. Neurosci Lett. 618:19–24. 2016. View Article : Google Scholar : PubMed/NCBI

40 

Donato AJ, Magerko KA, Lawson BR, Durrant JR, Lesniewski LA and Seals DR: SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J Physiol. 589:4545–4554. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Yang X, Li Y, Li Y, Ren X, Zhang X, Hu D, Gao Y, Xing Y and Shang H: Oxidative stress-mediated atherosclerosis: Mechanisms and therapies. Front Physiol. 8:6002017. View Article : Google Scholar : PubMed/NCBI

42 

Zhang M, Pan H, Xu Y, Wang X, Qiu Z and Jiang L: Allicin decreases lipopolysaccharide-induced oxidative stress and inflammation in human umbilical vein endothelial cells through suppression of mitochondrial dysfunction and activation of Nrf2. Cell Physiol Biochem. 41:2255–2267. 2017. View Article : Google Scholar : PubMed/NCBI

43 

Mukherjee N, Parida PK, Santra A, Ghosh T, Dutta A, Jana K, Misra AK and Sinha Babu SP: Oxidative stress plays major role in mediating apoptosis in filarial nematode Setaria cervi in the presence of trans-stilbene derivatives. Free Radic Biol Med. 93:130–144. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Wang XL, Wang X, Xiong LL, Zhu Y, Chen HL, Chen JX, Wang XX, Li RL, Guo ZY, Li P, et al: Salidroside improves doxorubicin-induced cardiac dysfunction by suppression of excessive oxidative stress and cardiomyocyte apoptosis. J Cardiovasc Pharmacol. 62:512–523. 2013. View Article : Google Scholar : PubMed/NCBI

45 

Sosnowska B, Mazidi M, Penson P, Gluba-Brzózka A, Rysz J and Banach M: The sirtuin family members SIRT1, SIRT3 and SIRT6: Their role in vascular biology and atherogenesis. Atherosclerosis. 265:275–282. 2017. View Article : Google Scholar : PubMed/NCBI

46 

Tsai KL, Hung CH, Chan SH, Hsieh PL, Ou HC, Cheng YH and Chu PM: Chlorogenic acid protects against oxLDL-induced oxida-tive damage and mitochondrial dysfunction by modulating SIRT1 in endothelial cells. Mol Nutr Food Res. 62:e17009282018. View Article : Google Scholar

47 

Chan SH, Hung CH, Shih JY, Chu PM, Cheng YH, Lin HC, Hsieh PL and Tsai KL: Exercise intervention attenuates hyper-homocysteinemia-induced aortic endothelial oxidative injury by regulating SIRT1 through mitigating NADPH oxidase/LOX-1 signaling. Redox Biol. 14:116–125. 2018. View Article : Google Scholar

48 

Zhu X, Yue H, Guo X, Yang J, Liu J, Liu J, Wang R and Zhu W: The preconditioning of berberine suppresses hydrogen peroxide-induced premature senescence via regulation of Sirtuin 1. Oxid Med Cell Longev. 2017:23918202017. View Article : Google Scholar : PubMed/NCBI

49 

Ballinger SW, Patterson C, Knight-Lozano CA, Burow DL, Conklin CA, Hu Z, Reuf J, Horaist C, Lebovitz R, Hunter GC, et al: Mitochondrial integrity and function in atherogenesis. Circulation. 106:544–549. 2002. View Article : Google Scholar : PubMed/NCBI

50 

Xing S, Yang X, Li W, Bian F, Wu D, Chi J, Xu G, Zhang Y and Jin S: Salidroside stimulates mitochondrial biogenesis and protects against H2O2-induced endothelial dysfunction. Oxid Med Cell Longev. 2014:9048342014. View Article : Google Scholar

51 

Xu MC, Shi HM, Wang H and Gao XF: Salidroside protects against hydrogen peroxide-induced injury in HUVECs via the regulation of REDD1 and mTOR activation. Mol Med Rep. 8:147–153. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Cai L, Li Y, Zhang Q, Sun H, Yan X, Hua T, Zhu Q, Xu H and Fu H: Salidroside protects rat liver against ischemia/reperfusion injury by regulating the GSK-3β/Nrf2-dependent antioxidant response and mitochondrial permeability transition. Eu J Pharmacol. 806:32–42. 2017. View Article : Google Scholar

53 

Dolinsky VW: The role of sirtuins in mitochondrial function and doxorubicin-induced cardiac dysfunction. Biol Chem. 398:955–974. 2017. View Article : Google Scholar : PubMed/NCBI

54 

Tang BL: Sirt1 and the Mitochondria. Mol Cells. 39:87–95. 2016. View Article : Google Scholar : PubMed/NCBI

55 

Feng Ma S, Zhang J, Chen R, Han J, Li D, Yang X, Li B, Fan X, Li MC, et al: SIRT1 activation by resveratrol alleviates cardiac dysfunction via mitochondrial regulation in diabetic cardiomyopathy mice. Oxid Med Cell Longev. 2017:46027152017.PubMed/NCBI

56 

Bairwa SC, Parajuli N and Dyck JR: The role of AMPK in cardiomyocyte health and survival. Biochim Biophys Acta. 1862:2199–2210. 2016. View Article : Google Scholar : PubMed/NCBI

57 

Shirwany NA and Zou MH: AMPK in cardiovascular health and disease. Acta Pharmacol Sin. 31:1075–1084. 2010. View Article : Google Scholar : PubMed/NCBI

58 

Gao F, Chen J and Zhu H: A potential strategy for treating atherosclerosis: Improving endothelial function via AMP-activated protein kinase. Sci China Life Sci. 61:1024–1029. 2018. View Article : Google Scholar : PubMed/NCBI

59 

Ewart MA and Kennedy S: AMPK and vasculoprotection. Pharmacol Ther. 131:242–253. 2011. View Article : Google Scholar

60 

Zheng T, Yang X, Li W, Wang Q, Chen L, Wu D, Bian F, Xing S and Jin S: Salidroside attenuates high-fat diet-induced nonalcoholic fatty liver disease via AMPK-dependent TXNIP/NLRP3 pathway. Oxid Med Cell Longev. 2018:85978972018. View Article : Google Scholar : PubMed/NCBI

61 

Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F and Ido Y: AMPK and SIRT1: A long-standing partnership. Am J Physiol Endocrinol Metab. 298:E751–E760. 2010. View Article : Google Scholar : PubMed/NCBI

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June 2019
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Copy and paste a formatted citation
APA
Zhao, D., Sun, X., Lv, S., Sun, M., Guo, H., Zhai, Y. ... Wang, X. (2019). Salidroside attenuates oxidized low‑density lipoprotein‑induced endothelial cell injury via promotion of the AMPK/SIRT1 pathway. International Journal of Molecular Medicine, 43, 2279-2290. https://doi.org/10.3892/ijmm.2019.4153
MLA
Zhao, D., Sun, X., Lv, S., Sun, M., Guo, H., Zhai, Y., Wang, Z., Dai, P., Zheng, L., Ye, M., Wang, X."Salidroside attenuates oxidized low‑density lipoprotein‑induced endothelial cell injury via promotion of the AMPK/SIRT1 pathway". International Journal of Molecular Medicine 43.6 (2019): 2279-2290.
Chicago
Zhao, D., Sun, X., Lv, S., Sun, M., Guo, H., Zhai, Y., Wang, Z., Dai, P., Zheng, L., Ye, M., Wang, X."Salidroside attenuates oxidized low‑density lipoprotein‑induced endothelial cell injury via promotion of the AMPK/SIRT1 pathway". International Journal of Molecular Medicine 43, no. 6 (2019): 2279-2290. https://doi.org/10.3892/ijmm.2019.4153