Quercetin has a protective effect on atherosclerosis via enhancement of autophagy in ApoE‑/‑ mice

Cao,Hui; Jia,Qingling; Shen,Dingzhu; Yan,Li; Chen,Chuan; Xing,Sanli

doi:10.3892/etm.2019.7851

Quercetin has a protective effect on atherosclerosis via enhancement of autophagy in ApoE‑/‑ mice

Authors:
- Hui Cao
- Qingling Jia
- Dingzhu Shen
- Li Yan
- Chuan Chen
- Sanli Xing
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Affiliations: Geriatrics Laboratory, Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, P.R. China
Published online on: August 5, 2019 https://doi.org/10.3892/etm.2019.7851
Pages: 2451-2458
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study examined the involvement of autophagy as a mechanism in the protective effect of quercetin (QUE) on atherosclerosis (AS) in ApoE‑/‑ mice. An AS model was established by feeding ApoE‑/‑ mice a high‑fat diet (HFD). Mice were divided into four experimental groups: The model, QUE, 3‑methyladenine (3‑MA) and QUE + 3‑MA groups. Additionally, age‑matched wild‑type C57BL/6 mice were used as a Control group. Autophagosomes in the aorta were examined using a transmission electron microscope. Aorta pathology, serum lipid accumulation and collagen deposition were determined by hematoxylin and eosin, Oil Red O and Masson staining, respectively. The levels of cytokines, including tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β) and interleukin‑18 (IL‑18) were measured using ELISA assays. Protein levels of mTOR, microtubule associated protein 1 light chain 3a (LC3), P53 and cyclin dependent kinase inhibitor 1A (P21) in the aorta were analyzed using western blotting. ApoE‑/‑ mice which were fed HFD exhibited substantial AS pathology, no autophagosomes, higher levels of TNF‑α, IL‑1β, IL‑18 and mTOR and lower ratios of LC3 II/I. All these alterations were ameliorated and aggravated by QUE and 3‑MA treatment, respectively. The inhibition of AS by QUE may be associated with the enhancement of autophagy and upregulation of P21 and P53 expression.

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1	Ross R: Atherosclerosis-an inflammatory disease. N Engl J Med. 340:115–126. 1999. View Article : Google Scholar : PubMed/NCBI
2	Grootaert MOJ, Lynn R, Schrijvers DM, De Meyer GRY and Martinet W: Defective autophagy in atherosclerosis: To die or to senesce? Oxid Med Cell Longe 2018. 76870832018.
3	Wang JC and Bennett M: Aging and atherosclerosis: Mechanisms, functional consequences, and potential therapeutics for cellular senescence. Cir Res. 111:245–259. 2012. View Article : Google Scholar
4	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.PubMed/NCBI
5	Kim YY, Jee HJ, Um JH, Kim YM, Bae SS and Yun J: Cooperation between p21 and Akt is required for p53-dependent cellular senescence. Aging Cell. 16:1094–1103. 2017. View Article : Google Scholar : PubMed/NCBI
6	Kitada M, Ogura Y and Koya D: The protective role of Sirt1 in vascular tissue: Its relationship to vascular aging and atherosclerosis. Aging (Albany NY). 8:2290–2307. 2016. View Article : Google Scholar : PubMed/NCBI
7	Netea-Maier RT, Plantinga TS, van de Veerdonk FL, Smit JW and Netea MG: Modulation of inflammation by autophagy: Consequences for human disease. Autophagy. 12:245–260. 2016. View Article : Google Scholar : PubMed/NCBI
8	Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, et al: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 12:1–222. 2016. View Article : Google Scholar : PubMed/NCBI
9	Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, Tzatsos A, Ozsolak F, Milos P, Ferrari F, et al: The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 468:659–663. 2010. View Article : Google Scholar : PubMed/NCBI
10	Jacquin E, Leclerc-Mercier S, Judon C, Blanchard E, Fraitag S and Florey O: Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation. Autophagy. 13:854–867. 2017. View Article : Google Scholar : PubMed/NCBI
11	Li C, Zhang WJ and Frei B: Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction. Redox Biol. 9:104–113. 2016. View Article : Google Scholar : PubMed/NCBI
12	Bhaskar S, Sudhakaran PR and Helen A: Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-κB signaling pathway. Cell Immunol. 310:131–140. 2016. View Article : Google Scholar : PubMed/NCBI
13	Cui Y, Hou P, Li F, Liu Q, Qin S, Zhou G, Xu X, Si Y and Guo S: Quercetin improves macrophage reverse cholesterol transport in apolipoprotein E-deficient mice fed a high-fat diet. Lipids Health Dis. 16:92017. View Article : Google Scholar : PubMed/NCBI
14	Li S, Cao H, Shen D, Jia Q, Chen C and Xing SL: Quercetin protects against ox-LDL-induced injury via regulation of ABCAl, LXR-α and PCSK9 in RAW264.7 macrophages. Mol Med Rep. 18:799–806. 2018.PubMed/NCBI
15	Zhi K, Li M, Bai J, Wu Y, Zhou S, Zhang X and Qu L: Quercitrin treatment protects endothelial progenitor cells from oxidative damage via inducing autophagy through extracellular signal-regulated kinase. Angiogenesis. 19:311–324. 2016. View Article : Google Scholar : PubMed/NCBI
16	Wang J: Guide for the care and use of medical laboratory animals. Shanghai Sci Tech Publishers; 2012
17	Xiye F: Medical laboratory zoology. People's Health Press. 156:1995.
18	Wu X, He L, Chen F, He X, Cai Y, Zhang G, Yi Q, He M and Luo J: Impaired autophagy contributes to adverse cardiac remodeling in acute myocardial infarction. PLoS One. 9:e1128912014. View Article : Google Scholar : PubMed/NCBI
19	Zimmer S, Grebe A, Bakke SS, Bode N, Halvorsen B, Ulas T, Skjelland M, De Nardo D, Labzin LI, Kerksiek A, et al: Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Medi. 8:333ra502016. View Article : Google Scholar
20	Kwon Y, Kim JW, Jeoung JA, Kim MS and Kang C: Autophagy is pro-senescence when seen in close-up, but anti-senescence in long-shot. Mol Cells. 40:607–612. 2017.PubMed/NCBI
21	Fernández ÁF, Sebti S, Wei Y, Zou Z, Shi M, McMillan KL, He C, Ting T, Liu Y, Chiang WC, et al: Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature. 558:136–140. 2018. View Article : Google Scholar : PubMed/NCBI
22	Revuelta M and Matheu A: Autophagy in stem cell aging. Aging Cell. 16:912–915. 2017. View Article : Google Scholar : PubMed/NCBI
23	Xiong Y, Yepuri G, Forbiteh M, Yu Y, Montani JP, Yang Z and Ming XF: ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA/AMPK signaling in advanced atherosclerosis. Autophagy. 10:2223–2238. 2014. View Article : Google Scholar : PubMed/NCBI
24	Tai S, Hu XQ, Peng DQ, Zhou SH and Zheng XL: The roles of autophagy in vascular smooth muscle cells. Int J Cardiol. 211:1–6. 2016. View Article : Google Scholar : PubMed/NCBI
25	Grootaert MO, da Costa Martins PA, Bitsch N, Pintelon I, De Meyer GR, Martinet W and Schrijvers DM: Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis. Autophagy. 11:2014–2032. 2015. View Article : Google Scholar : PubMed/NCBI
26	Yuan HX, Russell RC and Guan KL: Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy. 9:1983–1995. 2013. View Article : Google Scholar : PubMed/NCBI
27	Lu J, Shen Y, Qian HY, Liu LJ, Zhou BC, Xiao Y, Mao JN, An GY, Rui MZ, Wang T and Zhu CL: Effects of mild hypothermia on the ROS and expression of caspase-3 mRNA and LC3 of hippocampus nerve cells in rats after cardiopulmonary resuscitation. World J Emerg Med. 5:298–305. 2014. View Article : Google Scholar : PubMed/NCBI
28	Tran D, Bergholz J, Zhang H, He H, Wang Y, Zhang Y, Li Q, Kirkland JL and Xiao ZX: Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell. 13:669–678. 2014. View Article : Google Scholar : PubMed/NCBI
29	Si X, Shao C, Li J, Jia S, Tang W, Zhang J, Yang J, Wu X and Luo Y: Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency. Int J Biol Sci. 14:165–177. 2018. View Article : Google Scholar : PubMed/NCBI
30	ten Kate GL, Sijbrands EJ, Staub D, Coll B, ten Cate FJ, Feinstein SB and Schinkel AF: Noninvasive imaging of the vulnerable atherosclerotic plaque. Curr Probl Cardiol. 35:556–591. 2010. View Article : Google Scholar : PubMed/NCBI
31	Lee AS, Kim JS, Lee YJ, Kang DG and Lee HS: Anti-TNF-α activity of Portulaca oleracea in vascular endothelial cells. Int J Mol Sci. 13:5628–5644. 2012. View Article : Google Scholar : PubMed/NCBI
32	Liu Z, Lerman LO, Tang H, Barber C, Wan L, Hui MM, Furenlid LR and Woolfenden JM: Inflammation imaging of atherosclerosis in Apo-E-deficient mice using a (99m)Tc-labeled dual-domain cytokine ligand. Nucl Med Biol. 41:785–792. 2014. View Article : Google Scholar : PubMed/NCBI
33	Şahin M, Ugan Y, Tunç ŞE, Akın Ş, Köroğlu B, Kutlucan A, Sütçü R, Yeşildağ A and Kılbaş A: Potential role of interleukin-18 in patients with rheumatoid arthritis-associated carotid intima-media thickness but not insulin resistance. Eur J Rheumatol. 1:135–139. 2014. View Article : Google Scholar : PubMed/NCBI
34	Li Z, Wang G, Feng D, Zu G, Li Y, Shi X, Zhao Y, Jing H, Ning S, Le W, et al: Targeting the miR-665-3p-ATG4B-autophagy axis relieves inflammation and apoptosis in intestinal ischemia/reperfusion. Cell Death Dis. 9:4832018. View Article : Google Scholar : PubMed/NCBI
35	Peng S, Xu LW, Che XY, Xiao QQ, Pu J, Shao Q and He B: Atorvastatin inhibits inflammatory response, attenuates lipid deposition, and improves the stability of vulnerable atherosclerotic plaques by modulating autophagy. Front Pharmacol. 9:4382018. View Article : Google Scholar : PubMed/NCBI
36	Zhang M, Xie Z, Gao W, Pu L, Wei J and Guo C: Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats. Nutr Res. 36:271–279. 2016. View Article : Google Scholar : PubMed/NCBI
37	Sun X, Yamasaki M, Katsube T and Shiwaku K: Effects of quercetin derivatives from mulberry leaves: Improved gene expression related hepatic lipid and glucose metabolism in short-term high-fat fed mice. Nutr Res Pract. 9:137–143. 2015. View Article : Google Scholar : PubMed/NCBI
38	Yang D, Liu X, Liu M, Chi H, Liu J and Han H: Protective effects of quercetin and taraxasterol against H₂O₂-induced human umbilical vein endothelial cell injury in vitro. Exp Ther Med. 10:1253–1260. 2015. View Article : Google Scholar : PubMed/NCBI
39	Liu L, Gao C, Yao P and Gong Z: Quercetin alleviates high-fat diet-induced oxidized low-density lipoprotein accumulation in the liver: Implication for autophagy regulation. Biomed Res Int 2015. 6075312015.
40	Qu L, Xiao-Chun L, Gu B, Zhang H, Dai W and SHI Y: Quercetin up-regulates autophagy in RSC96 cells culutured in high glucose via the pathway of Akt-Mtor. Basic Clin Med. 5:596–602. 2015.