SIRT4 suppresses the PI3K/Akt/NF‑κB signaling pathway and attenuates HUVEC injury induced by oxLDL

Tao,Yu; Yu,Songping; Chao,Min; Wang,Yang; Xiong,Jianhua; Lai,Hengli

doi:10.3892/mmr.2019.10161

SIRT4 suppresses the PI3K/Akt/NF‑κB signaling pathway and attenuates HUVEC injury induced by oxLDL

Authors:
- Yu Tao
- Songping Yu
- Min Chao
- Yang Wang
- Jianhua Xiong
- Hengli Lai
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Affiliations: Department of Cardiology, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 330006, P.R. China, Department of Internal Medicine, Shanggao Hospital of Traditional Chinese Medicine, Yichun, Jiangxi 336400, P.R. China, Dexing Hospital of Traditional Chinese Medicine, Dexing, Jiangxi 334200, P.R. China, Department of Geriatrics, Fuzhou First People's Hospital, Fuzhou, Jiangxi 344000, P.R. China
Published online on: April 12, 2019 https://doi.org/10.3892/mmr.2019.10161
Pages: 4973-4979

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Abstract

Atherosclerosis is a chronic and progressive disease. Its morbidity and mortality rates have demonstrated an increase in recent years. The present study aimed to explore the role of sirtuin (SIRT) 4 in the development of atherosclerosis. Alterations in SIRT4 expression in response to oxidized low density lipoprotein (oxLDL) were quantified in human umbilical vein endothelial cells (HUVECs) using western blotting. Cell counting kit‑8 and ﬂow cytometry assays were used in order to explore the effects of SIRT4 on HUVEC proliferation and apoptosis. The effect of SIRT4 on the expression of inﬂammatory factors in HUVECs was analyzed using ELISA. The expression and phosphorylation of proteins in the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)/nuclear factor (NF)‑κB pathway were comparatively analyzed using western blotting. Nuclear translocation of p65 NF‑κB was examined using immunofluorescence. The present study indicated that oxLDL treatment decreased the expression of SIRT4 in HUVECs in a dose‑ and time‑dependent manner. SIRT4 overexpression promoted oxLDL‑induced HUVEC proliferation and inhibited cell apoptosis. Furthermore, SIRT4 overexpression suppressed the PI3K/Akt/NF‑κB pathway by inhibiting PI3K phosphorylation and phosphorylated (p)‑Akt, p‑nuclear factor of kappa light polypeptide gene enhancer in B‑cells inhibitor α and p‑p65 NF‑κB expression; blocking p65 NF‑κB nuclear translocation and decreasing interleukin (IL)‑1β, IL‑6, and tumor necrosis factor α expression in oxLDL‑induced HUVECs. In conclusion, SIRT4 overexpression enhanced HUVEC survival, suppressed the PI3K/Akt/NF‑κB signaling pathway and inhibited the expression of inflammatory cytokines in oxLDL‑induced HUVECs.

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1	Heuslein JL, Meisner JK, Li X, Song J, Vincentelli H, Leiphart RJ, Ames EG, Blackman BR, Blackman BR and Price RJ: Mechanisms of amplified arteriogenesis in collateral artery segments exposed to reversed flow direction. Arterioscler Thromb Vasc Biol. 35:2354–2365. 2015. View Article : Google Scholar : PubMed/NCBI
2	Tousoulis D, Oikonomou E, Economou EK, Crea F and Kaski JC: Inflammatory cytokines in atherosclerosis: Current therapeutic approaches. Eur Heart J. 37:1723–1732. 2016. View Article : Google Scholar : PubMed/NCBI
3	Park KH and Park WJ: Endothelial dysfunction: Clinical implications in cardiovascular disease and therapeutic approaches. J Korean Med Sci. 30:1213–1225. 2015. View Article : Google Scholar : PubMed/NCBI
4	Tuttolomondo A, Di Raimondo D, Pecoraro R, Arnao V, Pinto A and Licata G: Atherosclerosis as an inflammatory disease. Curr Pharm Des. 18:4266–4288. 2012. View Article : Google Scholar : PubMed/NCBI
5	Chistiakov DA, Melnichenko AA, Grechko AV, Myasoedova VA and Orekhov AN: Potential of anti-inflammatory agents for treatment of atherosclerosis. Exp Mol Pathol. 104:114–124. 2018. View Article : Google Scholar : PubMed/NCBI
6	Ren K, Lu YJ, Mo ZC, -Liu X, Tang ZL, Jiang Y, Peng XS, Li L, Zhang QH and Yi GH: ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs. J Physiol Biochem. 73:287–296. 2017. View Article : Google Scholar : PubMed/NCBI
7	Pirinen E, Lo Sasso G and Auwerx J: Mitochondrial sirtuins and metabolic homeostasis. Best Pract Res Clin Endocrinol Metab. 26:759–770. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kane AE and Sinclair DA: Sirtuins and NAD(+) in the development and treatment of metabolic and cardiovascular diseases. Circ Res. 123:868–885. 2018. View Article : Google Scholar : PubMed/NCBI
9	Zheng H, Fu Y, Huang Y, Zheng X, Yu W and Wang W: mTOR signaling promotes foam cell formation and inhibits foam cell egress through suppressing the SIRT1 signaling pathway. Mol Med Rep. 16:3315–3323. 2017. View Article : Google Scholar : PubMed/NCBI
10	D'Onofrio N, Servillo L and Balestrieri ML: SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection. Antioxid Redox Signal. 28:711–732. 2018. View Article : Google Scholar : PubMed/NCBI
11	Zhang B, Ma Y and Xiang C: SIRT2 decreases atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice by modulating macrophage polarization. Biomed Pharmacother. 97:1238–1242. 2018. View Article : Google Scholar : PubMed/NCBI
12	Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, et al: SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 126:941–954. 2006. View Article : Google Scholar : PubMed/NCBI
13	Komlos D, Mann KD, Zhuo Y, Ricupero CL, Hart RP, Liu AY and Firestein BL: Glutamate dehydrogenase 1 and SIRT4 regulate glial development. Glia. 61:394–408. 2013. View Article : Google Scholar : PubMed/NCBI
14	Michishita E, Park JY, Burneskis JM, Barrett JC and Horikawa I: Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 16:4623–4635. 2005. View Article : Google Scholar : PubMed/NCBI
15	Laurent G, de Boer VC, Finley LW, Sweeney M, Lu H, Schug TT, Cen Y, Jeong SM, Li X, Sauve AA and Haigis MC: SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Mol Cell Biol. 33:4552–4561. 2013. View Article : Google Scholar : PubMed/NCBI
16	Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, et al: SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell. 50:686–698. 2013. View Article : Google Scholar : PubMed/NCBI
17	Qiu Y, Lai H, Huang Y, Hong L, Wang H and Tao Y: Effect of shear force on SIRT4 in LPS-injured human umbilical vein endothelial cells. Int J Clin Exp Pathol. 9:4921–4930. 2016.
18	Miyo M, Yamamoto H, Konno M, Colvin H, Nishida N, Koseki J, Kawamoto K, Ogawa H, Hamabe A, Uemura M, et al: Tumour-suppressive function of SIRT4 in human colorectal cancer. Br J Cancer. 113:492–499. 2015. View Article : Google Scholar : PubMed/NCBI
19	Shi JX, Wang QJ, Li H and Huang Q: SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis. Exp Ther Med. 13:342–348. 2017. View Article : Google Scholar : PubMed/NCBI
20	Tao Y, Huang C, Huang Y, Hong L, Wang H, Zhou Z and Qiu Y: SIRT4 suppresses inflammatory responses in human umbilical vein endothelial cells. Cardiovasc Toxicol. 15:217–223. 2015. View Article : Google Scholar : PubMed/NCBI
21	Hasanally D, Edel A, Chaudhary R and Ravandi A: Identification of oxidized phosphatidylinositols present in OxLDL and human atherosclerotic plaque. Lipids. 52:11–26. 2017. View Article : Google Scholar : PubMed/NCBI
22	Kang Q, Liu W, Liu H and Zhou M: Effect of compound chuanxiong capsule on inflammatory reaction and PI3K/Akt/NF-κB signaling pathway in atherosclerosis. Evid Based Complement Alternat Med. 2015:5845962015. View Article : Google Scholar : PubMed/NCBI
23	Schlegel N, Leweke R, Meir M, Germer CT and Waschke J: Role of NF-κB activation in LPS-induced endothelial barrier breakdown. Histochem Cell Biol. 138:627–641. 2012. View Article : Google Scholar : PubMed/NCBI
24	Liu Z, Wang J, Huang X, Li Z and Liu P: Deletion of sirtuin 6 accelerates endothelial dysfunction and atherosclerosis in apolipoprotein E-deficient mice. Transl Res. 172:18–29.e2. 2016. View Article : Google Scholar : PubMed/NCBI
25	Jackson SW, Scharping NE, Jacobs HM, Wang S, Chait A and Rawlings DJ: Cutting Edge: BAFF overexpression reduces atherosclerosis via TACI-Dependent B cell activation. J Immunol. 197:4529–4534. 2016. View Article : Google Scholar : PubMed/NCBI
26	Min J, Weitian Z, Peng C, Yan P, Bo Z, Yan W, Yun B and Xukai W: Correlation between insulin-induced estrogen receptor methylation and atherosclerosis. Cardiovasc Diabetol. 15:1562016. View Article : Google Scholar : PubMed/NCBI
27	Di Pietro N, Formoso G and Pandolfi A: Physiology and pathophysiology of oxLDL uptake by vascular wall cells in atherosclerosis. Vascul Pharmacol. 84:1–7. 2016. View Article : Google Scholar : PubMed/NCBI
28	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
29	Garat CV, Crossno JT Jr, Sullivan TM, Reusch JE and Klemm DJ: Inhibition of phosphatidylinositol 3-kinase/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells. J Cardiovasc Pharmacol. 62:539–548. 2013. View Article : Google Scholar : PubMed/NCBI
30	Shen T, Yang Z, Cheng X, Xiao Y, Yu K, Cai X, Xia C and Li Y: CXCL8 induces epithelial-mesenchymal transition in colon cancer cells via the PI3K/Akt/NF-κB signaling pathway. Oncol Rep. 37:2095–2100. 2017. View Article : Google Scholar : PubMed/NCBI
31	Napetschnig J and Wu H: Molecular basis of NF-κB signaling. Annu Rev Biophys. 42:443–468. 2013. View Article : Google Scholar : PubMed/NCBI
32	Hayden MS and Ghosh S: NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 26:203–234. 2012. View Article : Google Scholar : PubMed/NCBI
33	Onat D, Brillon D, Colombo PC and Schmidt AM: Human vascular endothelial cells: A model system for studying vascular inflammation in diabetes and atherosclerosis. Curr Diab Rep. 11:193–202. 2011. View Article : Google Scholar : PubMed/NCBI
34	Zernecke A and Weber C: Inflammatory mediators in atherosclerotic vascular disease. Basic Res Cardiol. 100:93–101. 2005. View Article : Google Scholar : PubMed/NCBI