The Role of Leukemia Inhibitory Factor in Cardiovascular Disease: Signaling in Inflammation, Coagulation, and Angiogenesis
Abstract
Background: Cardiovascular disease (CVD) is one of the principal causes of mortality in the world. Various factors have been identified in the pathogenesis of CVD. Leukemia inhibitory factor (LIF) as a secretory cytokine is one of these factors. The LIF receptor is located on endothelial cells and plays a role in the expression of specific genes in these cells. Endothelial cells are the innermost cells of blood vessels, and defects in these cells cause endothelial dysfunction and eventually CVD.
Methods: The present study is based on PubMed database information (1982–2022) using the following words: “cardiovascular disease,” “endothelial cells,” “leukemia inhibitory factor,” and “angiogenesis.”
Results: LIF can cause arteriosclerotic plaques by activating inflammatory mechanisms in monocytes through the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. LIF can also induce vascular endothelial growth factor expression by activating signaling pathways, eventually leading to angiogenesis. Additionally, it can activate the coagulation cascade by factor VII production promotion within endothelial cells.
Conclusion Understanding the interplay between LIF and the inflammation pathways, coagulation, and angiogenesis as key factors in CVD occurrence raises the possibility of targeting this factor as a potential strategy to mitigate CVD risk.
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2. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation 2020;141:e139-e596.
3. Schwartz SM, Schwartz HT, Horvath S, Schadt E, Lee SI. A systematic approach to multifactorial cardiovascular disease: causal analysis. Arterioscler Thromb Vasc Biol 2012;32:2821-2835.
4. Zhao L, Varghese Z, Moorhead JF, Chen Y, Ruan XZ. CD36 and lipid metabolism in the evolution of atherosclerosis. Br Med Bull. 2018 Jun 1;126(1):101-112.
5. Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet 2017;18:331-344.
6. Sayols-Baixeras S, Lluís-Ganella C, Lucas G, Elosua R. Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants. Appl Clin Genet 2014;7:15-32.
7. Bauer AJ, Martin KA. Coordinating Regulation of Gene Expression in Cardiovascular Disease: Interactions between Chromatin Modifiers and Transcription Factors. Front Cardiovasc Med 2017;4:19.
8. McCulley DJ, Black BL. Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 2012;100:253-277.
9. Barthelmes J, Nägele MP, Ludovici V, Ruschitzka F, Sudano I, Flammer AJ. Endothelial dysfunction in cardiovascular disease and Flammer syndrome-similarities and differences. EPMA J 2017;8:99-109.
10. Yue X, Wu L, Hu W. The regulation of leukemia inhibitory factor. Cancer Cell Microenviron 2015;2:e877.
11. Jiang W, Bai W, Li J, Liu J, Zhao K, Ren L. Leukemia inhibitory factor is a novel biomarker to predict lymph node and distant metastasis in pancreatic cancer. Int J Cancer 2021;148:1006-1013.
12. Mohri T, Fujio Y, Maeda M, Ito T, Iwakura T, Oshima Y, Uozumi Y, Segawa M, Yamamoto H, Kishimoto T, Azuma J. Leukemia inhibitory factor induces endothelial differentiation in cardiac stem cells. J Biol Chem 2006;281:6442-6447.
13. Suman P, Malhotra SS, Gupta SK. LIF-STAT signaling and trophoblast biology. JAKSTAT 2013;2:e25155.
14. Krüger-Genge A, Blocki A, Franke RP, Jung F. Vascular Endothelial Cell Biology: An Update. Int J Mol Sci 2019;20:4411.
15. Eelen G, de Zeeuw P, Treps L, Harjes U, Wong BW, Carmeliet P. Endothelial Cell Metabolism. Physiol Rev 2018;98:3-58.
16. Cong X, Kong W. Endothelial tight junctions and their regulatory signaling pathways in vascular homeostasis and disease. Cell Signal 2020;66:109485.
17. Eelen G, de Zeeuw P, Simons M, Carmeliet P. Endothelial cell metabolism in normal and diseased vasculature. Circ Res 2015;116:1231-44.
18. Sturtzel C. Endothelial Cells. Adv Exp Med Biol 2017;1003:71-91.
19. Ando J, Yamamoto K. Flow detection and calcium signalling in vascular endothelial cells. Cardiovasc Res 2013;99:260-268.
20. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003;23:168-175.
21. Sun HJ, Wu ZY, Nie XW, Bian JS. Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide. Front Pharmacol 2020;10:1568.
22. Chen Q, Lv J, Yang W, Xu B, Wang Z, Yu Z, Wu J, Yang Y, Han Y. Targeted inhibition of STAT-3 as a potential treatment strategy for atherosclerosis. Theranostics 2019;9:6424-6442.
23. Lusis AJ. Atherosclerosis. Nature 2000;407:233-241.
24. Förstermann U, Xia N, Li H. Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis. Circ Res 2017;120:713-735.
25. Menghini R, Casagrande V, Cardellini M, Ballanti M, Davato F, Cardolini I, Stoehr R, Fabrizi M, Morelli M, Anemona L, Bernges I, Schwedhelm E, Ippoliti A, Mauriello A, Böger RH, Federici M. FoxO1 regulates asymmetric dimethylarginine via downregulation of dimethylaminohydrolase 1 in human endothelial cells and subjects with atherosclerosis. Atherosclerosis 2015;242:230-235.
26. Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, Luo S, Li Z, Liu P, Han J, Harding IC, Ebong EE, Cameron SJ, Stewart AG, Weng J. Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies. Pharmacol Rev 2021;73:924-967.
27. Auernhammer CJ, Melmed S. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Endocr Rev 2000;21:313-345.
28. Knight RA, Scarabelli TM, Stephanou A. STAT transcription in the ischemic heart. JAKSTAT 2012;1:111-117.
29. Wang Z, Ni L, Wang J, Lu C, Ren M, Han W, Liu C. The protective effect of melatonin on smoke-induced vascular injury in rats and humans: a randomized controlled trial. J Pineal Res 2016;60:217-227.
30. Wolinsky H. A proposal linking clearance of circulating lipoproteins to tissue metabolic activity as a basis for understanding atherogenesis. Circ Res 1980;47:301-311.
31. Birukov KG. Small GTPases in mechanosensitive regulation of endothelial barrier. Microvasc Res 2009;77:46-52.
32. Ng IH, Yeap YY, Ong LS, Jans DA, Bogoyevitch MA. Oxidative stress impairs multiple regulatory events to drive persistent cytokine-stimulated STAT-3 phosphorylation. Biochim Biophys Acta 2014;1843:483-494.
33. Nicola NA, Babon JJ. Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 2015;26:533-544.
34. Cao Z, Liao Q, Su M, Huang K, Jin J, Cao D. AKT and ERK dual inhibitors: The way forward? Cancer Lett 2019;459:30-40.
35. Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 1997;15:797-819.
36. Fiordelisi A, Iaccarino G, Morisco C, Coscioni E, Sorriento D. NFkappaB is a Key Player in the Crosstalk between Inflammation and Cardiovascular Diseases. Int J Mol Sci 2019;20:1599.
37. Sulciner DJ, Irani K, Yu ZX, Ferrans VJ, Goldschmidt-Clermont P, Finkel T. rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation. Mol Cell Biol 1996;16:7115-7121.
38. Tone E, Kunisada K, Fujio Y, Matsui H, Negoro S, Oh H, Kishimoto T, Yamauchi-Takihara K. Angiotensin II interferes with leukemia inhibitory factor-induced STAT-3 activation in cardiac myocytes. Biochem Biophys Res Commun1 19981;2531:147-150.
39. Minguet S, Huber M, Rosenkranz L, Schamel WW, Reth M, Brummer T. Adenosine and cAMP are potent inhibitors of the NF-kappa B pathway downstream of immunoreceptors. Eur J Immunol 2005;35:31-41.
40. Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF-κB in the heart: to be or not to NF-κB. Circ Res 2011;108:1122-1132.
41. Ke Y, Zebda N, Oskolkova O, Afonyushkin T, Berdyshev E, Tian Y, Meng F, Sarich N, Bochkov VN, Wang JM, Birukova AA, Birukov KG. Anti-Inflammatory Effects of OxPAPC Involve Endothelial Cell-Mediated Generation of LXA4. Circ Res 2017;121:244-257.
42. Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B. The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol 2002;22:1158-171.
43. Curry JM, Eubank TD, Roberts RD, Wang Y, Pore N, Maity A, Marsh CB. M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo. PLoS One 2008;3:e3405.
44. Eilken HM, Adams RH. Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 2010;22:617-625.
45. Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007;8:464-478.
46. Sewduth R, Santoro MM. "Decoding" Angiogenesis: New Facets Controlling Endothelial Cell Behavior. Front Physiol 2016;7:306.
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| Files | ||
| Issue | Vol 19 No 1 (2024): J Teh Univ Heart Ctr | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jthc.v19i1.15531 | |
| Keywords | ||
| Cardiovascular disease Endothelial cells Leukemia inhibitory factor Angiogenesis. | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Rezaeeyan H, Moghimian-Boroujeni B, Abdolalian M, Javan M. The Role of Leukemia Inhibitory Factor in Cardiovascular Disease: Signaling in Inflammation, Coagulation, and Angiogenesis. J Tehran Heart Cent. 2024;19(1):6-13.
