Atherosclerosis is a chronic inflammatory disease involving endothelial cells apoptosis, vascular smooth muscle cells proliferation and foam cells formation. Signal transduction and activator of transcription 3 (STAT3) participates in many life activities such as cell growth and apoptosis, and plays an important role in atherosclerosis. This article reviews the role of STAT3 in the development of atherosclerosis.

1. Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017[J]. Lancet, 2019, 394(10204): 1145-1158. DOI: 10.1016/S0140-6736(19)30427-1.

2. Ross R, Glomset JA. The pathogenesis of atherosclerosis (first of two parts)[J]. N Engl J Med, 1976, 295(7): 369-377. DOI: 10.1056/NEJM197608122950707.

3. Gharavi NM, Alva JA, Mouillesseaux KP, et al. Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo[J]. J Biol Chem, 2007, 282(43): 31460-31468. DOI: 10.1074/jbc.M704267200.

4. Wang X, Chen L, Liu J, et al. In vivo treatment of rat arterial adventitia with interleukin1beta induces intimal proliferation via the JAK2/STAT3 signaling pathway[J]. Mol Med Rep, 2016, 13(4): 3451-3458. DOI: 10.3892/mmr.2016.4982.

5. Chen M, Lechner J, Zhao J, et al. STAT3 activation in circulating monocytes contributes to neovascular age-related macular degeneration[J]. Curr Mol Med, 2016, 16(4): 412-423. DOI: 10.2174/1566524016666160324130031.

6. Daniel JM, Dutzmann J, Bielenberg W, et al. Inhibition of STAT3 signaling prevents vascular smooth muscle cell proliferation and neointima formation[J]. Basic Res Cardiol, 2012, 107(3): 261. DOI: 10.1007/s00395-012-0261-9.

7. Nakamura R, Sene A, Santeford A, et al. IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis[J]. Nat Commun, 2015, 6: 7847. DOI: 10.1038/ncomms8847.

8. Dal Monte M, Martini D, Ristori C, et al. Hypoxia effects on proangiogenic factors in human umbilical vein endothelial cells: functional role of the peptide somatostatin[J]. Naunyn Schmiedebergs Arch Pharmacol, 2011, 383(6): 593-612. DOI: 10.1007/s00210-011-0625-y.

9. Dutzmann J, Daniel JM, Bauersachs J, et al. Emerging translational approaches to target STAT3 signalling and its impact on vascular disease[J]. Cardiovasc Res, 2015, 106(3): 365-374. DOI: 10.1093/cvr/cvv103.

10.    Ganta VC, Choi M, Kutateladze A, et al. VEGF165b modulates endothelial VEGFR1-STAT3 signaling pathway and angiogenesis in human and experimental peripheral arterial disease[J]. Circ Res, 2017, 120(2): 282-295. DOI: 10.1161/CIRCRESAHA.116.309516.

11.    Albasanz-Puig A, Murray J, Preusch M, et al. Oncostatin M is expressed in atherosclerotic lesions: a role for Oncostatin M in the pathogenesis of atherosclerosis[J]. Atherosclerosis, 2011, 216(2): 292-298. DOI: 10.1016/j.atherosclerosis.2011.02.003.

12.    Zhong X, Ma X, Zhang L, et al. MIAT promotes proliferation and hinders apoptosis by modulating miR-181b/STAT3 axis in ox-LDL-induced atherosclerosis cell models[J]. Biomed Pharmacother, 2018, 97: 1078-1085. DOI: 10.1016/j.biopha.2017.11.052.

13.    Li S, Geng Q, Chen H, et al. The potential inhibitory effects of miR19b on vulnerable plaque formation via the suppression of STAT3 transcriptional activity[J]. Int J Mol Med, 2018, 41(2): 859-867. DOI: 10.3892/ijmm.2017.3263.

14.    Qin H, Holdbrooks AT, Liu Y, et al. SOCS3 deficiency promotes M1 macrophage polarization and inflammation[J]. J Immunol, 2012, 189(7): 3439-3448. DOI: 10.4049/jimmunol.1201168.

15.    Recio C, Oguiza A, Lazaro I, et al. Suppressor of cytokine signaling 1-derived peptide inhibits Janus kinase/signal transducers and activators of transcription pathway and improves inflammation and atherosclerosis in diabetic mice[J]. Arterioscler Thromb Vasc Biol, 2014, 34(9): 1953-1960. DOI: 10.1161/ATVBAHA.114.304144.

16.    Feuerborn R, Becker S, Poti F, et al. High density lipoprotein (HDL)-associated sphingosine 1-phosphate (S1P) inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression[J]. Atherosclerosis, 2017, 257: 29-37. DOI: 10.1016/j.atherosclerosis.2016.12.009.

17.    Xu S, Ni H, Chen H, et al. The interaction between STAT3 and nAChRα1 interferes with nicotine-induced atherosclerosis via Akt/mTOR signaling cascade[J]. Aging (Albany NY), 2019, 11(19): 8120-8138. DOI: 10.18632/aging.102296.

18.    Liu X, Tang Y, Cui Y, et al. Autophagy is associated with cell fate in the process of macrophage-derived foam cells formation and progress[J]. J Biomed Sci, 2016, 23(1): 57. DOI: 10.1186/s12929-016-0274-z.

19.    Grootaert MO, da Costa Martins PA, Bitsch N, et al. Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis[J]. Autophagy, 2015, 11(11): 2014-2032. DOI: 10.1080/15548627.2015.1096485.

20.    Liao X, Sluimer JC, Wang Y, et al. Macrophage autophagy plays a protective role in advanced atherosclerosis[J]. Cell Metab, 2012, 15(4): 545-553. DOI: 10.1016/j.cmet.2012.01.022.

21.    Razani B, Feng C, Coleman T, et al. Autophagy links inflammasomes to atherosclerotic progression[J]. Cell Metab, 2012, 15(4): 534-544. DOI: 10.1016/j.cmet.2012.02.011.

22.    Feng Y, Ke C, Tang Q, et al. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling[J]. Cell Death Dis, 2014, 5: e1088. DOI: 10.1038/cddis.2014.59.

23.    Pratt J, Annabi B. Induction of autophagy biomarker BNIP3 requires a JAK2/STAT3 and MT1-MMP signaling interplay in Concanavalin-A-activated U87 glioblastoma cells[J]. Cell Signal, 2014, 26(5): 917-924. DOI: 10.1016/j.cellsig.2014.01.012.

24.    Miao LJ, Huang FX, Sun ZT, et al. Stat3 inhibits Beclin 1 expression through recruitment of HDAC3 in nonsmall cell lung cancer cells[J]. Tumour Biol, 2014, 35(7): 7097-7103. DOI: 10.1007/s13277-014-1961-6.

25.    You L, Wang Z, Li H, et al. The role of STAT3 in autophagy[J]. Autophagy, 2015, 11(5): 729-739. DOI: 10.1080/15548627.2015.1017192.

26.    Aarup A, Pedersen TX, Junker N, et al. Hypoxia-Inducible Factor-1alpha Expression in Macrophages Promotes Development of Atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2016, 36(9): 1782-1790. DOI: 10.1161/ATVBAHA.116.307830.

27.    Kouroku Y, Fujita E, Tanida I, et al. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation[J]. Cell Death Differ, 2007, 14(2): 230-239. DOI: 10.1038/sj.cdd.4401984.

28.    Oh HM, Yu CR, Dambuza I, et al. STAT3 protein interacts with Class O Forkhead transcription factors in the cytoplasm and regulates nuclear/cytoplasmic localization of FoxO1 and FoxO3a proteins in CD4(+) T cells[J]. J Biol Chem, 2012, 287(36): 30436-30443. DOI: 10.1074/jbc.M112.359661.

29.    Horiguchi A, Asano T, Kuroda K, et al. STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma[J]. Br J Cancer, 2010, 102(11): 1592-1599. DOI: 10.1038/sj.bjc.6605691.

30.    Yang X, Jia J, Yu Z, et al. Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit[J]. BMC Cardiovasc Disord, 2020, 20(1): 133. DOI: 10.1186/s12872-020-01391-7.

31.    Plens-Galaska M, Szelag M, Collado A, et al. Genome-Wide inhibition of pro-atherogenic gene expression by multi-stat targeting compounds as a novel treatment strategy of CVDs[J]. Front Immunol, 2018, 9: 2141. DOI: 10.3389/fimmu.2018.02141.

32.    Loppnow H, Zhang L, Buerke M, et al. Statins potently reduce the cytokine-mediated IL-6 release in SMC/MNC cocultures[J]. J Cell Mol Med, 2011, 15(4): 994-1004. DOI: 10.1111/j.1582-4934.2010.01036.x.

33.    Horiuchi M, Cui TX, Li Z, et al. Fluvastatin enhances the inhibitory effects of a selective angiotensin II type 1 receptor blocker, valsartan, on vascular neointimal formation[J]. Circulation, 2003, 107(1): 106-112. DOI: 10.1161/01.cir.0000043244.13596.20.

34.    Fang T, Guo B, Xue L, et al. Atorvastatin prevents myocardial fibrosis in spontaneous hypertension via interleukin-6 (il-6)/signal transducer and activator of transcription 3 (STAT3)/Endothelin-1 (ET-1) pathway[J]. Med Sci Monit, 2019, 25: 318-323. DOI: 10.12659/MSM.912032.

35.    Interleukin-6 Receptor Mendelian Randomisation Analysis Consortium, Swerdlow DI, Holmes MV, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis[J]. Lancet, 2012, 379(9822): 1214-1224. DOI: 10.1016/S0140-6736(12)60110-X.

36.    McInnes IB, Thompson L, Giles JT, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study[J]. Ann Rheum Dis, 2015, 74(4): 694-702. DOI: 10.1136/annrheumdis-2013-204345.

37.    Protogerou AD, Zampeli E, Fragiadaki K, et al. A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis[J]. Atherosclerosis, 2011, 219(2): 734-736. DOI: 10.1016/j.atherosclerosis.2011.09.015.

38.    Kleveland O, Ueland T, Kunszt G, et al. Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1beta in non-ST-elevation myocardial infarction[J]. Int J Cardiol, 2018, 271: 1-7. DOI: 10.1016/j.ijcard.2018.04.136.

39.    Ueland T, Kleveland O, Michelsen AE, et al. Serum PCSK9 is modified by interleukin-6 receptor antagonism in patients with hypercholesterolaemia following non-ST-elevation myocardial infarction[J]. Open Heart, 2018, 5(2): e000765. DOI: 10.1136/openhrt-2017-000765.

40.    Cai T, Zhang Y, Ho YL, et al. Association of interleukin 6 receptor variant with cardiovascular disease effects of interleukin 6 receptor blocking therapy: a phenome-wide association study[J]. JAMA Cardiol, 2018, 3(9): 849-857. DOI: 10.1001/jamacardio.2018.2287.