Polish Journal of Pathology
eISSN: 2084-9869
ISSN: 1233-9687
Polish Journal of Pathology
Current issue Archive Manuscripts accepted About the journal Supplements Editorial board Abstracting and indexing Subscription Contact Instructions for authors Publication charge Ethical standards and procedures
Editorial System
Submit your Manuscript
SCImago Journal & Country Rank
Search
Editorial Policies
Sarajevo Declaration on Integrity and Visibility of Scholarly Publications

Open access

without publication fees
2/2025
vol. 76
 
Share:
Send email
Share:
Original paper

High mobility group box 1 attenuates aortic stenosis by modulating macrophages to reduce valvular calcification

Dong Zhao
1
,
Yun Zhao
1
,
Li-Na Luan
1

  1. Shanghai Geriatric Medical Centre, Shanghai, China
Pol J Pathol2025; 76 (2): 141-150
DOI: https://doi.org/10.5114/pjp.2025.153975
Online publish date: 2025/09/22
Article file
- PJP-03302.pdf  [0.87 MB]
Get citation
 
PlumX metrics:
 
1. Manning WJ. Asymptomatic aortic stenosis in the elderly: a clinical review. JAMA 2013; 310: 1490-1497.
2. Jain H, Goyal A, Khan ATMA, et al. Insights into calcific aor­tic valve stenosis: a comprehensive overview of the disease and advancing treatment strategies. Ann Med Surg (2012) 2024; 86: 3577-3590.
3. Lee SH, Choi JH. Involvement of inflammatory responses in the early development of calcific aortic valve disease: lessons from statin therapy. Anim Cells Syst (Seoul) 2018; 22: 390- 399.
4. Bossé Y, Miqdad A, Fournier D, Pépin A, Pibarot P, Mathieu P. Refining molecular pathways leading to calcific aortic valve ste­nosis by studying gene expression profile of normal and calci­fied stenotic human aortic valves. Circ Cardiovasc Genet 2009; 2: 489-498.
5. El Husseini D, Boulanger MC, Mahmut A, et al. P2Y2 recep­tor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease. J Mol Cell Car­diol 2014; 72: 146-156.
6. Swierszcz J, Dubiel JS, Krzysiek J, Sztefko K. One-year obser­vation of inflammatory markers in patients with aortic valve stenosis. J Heart Valve Dis 2011; 20: 639-649.
7. Li X, Lim J, Lu J, Pedego TM, Demer L, Tintut Y. Protective Role of Smad6 in Inflammation-Induced Valvular Cell Calcifi­cation. J Cell Biochem 2015; 116: 2354-2364.
8. Yu Z, Seya K, Daitoku K, Motomura S, Fukuda I, Furuka­wa K. Tumor necrosis factor-a accelerates the calcification of human aortic valve interstitial cells obtained from patients with calcific aortic valve stenosis via the BMP2-Dlx5 pathway. J Pharmacol Exp Ther 2011; 337: 16-23.
9. Weiss RM, Miller JD, Heistad DD. Fibrocalcific aortic valve disease: opportunity to understand disease mechanisms using mouse models. Circ Res 2013; 113: 209-222.
10. Wang H, Leinwand LA, Anseth KS. Cardiac valve cells and their microenvironment – insights from in vitro studies. Nat Rev Cardiol 2014; 11: 715-727.
11. Lee SH, Choi JH. Involvement of Immune Cell Network in Aortic Valve Stenosis: Communication between Valvular In­terstitial Cells and Immune Cells. Immune Netw 2016; 16: 26-32.
12. Leopold JA. Cellular mechanisms of aortic valve calcification. Circ Cardiovasc Interv 2012; 5: 605-614.
13. Alexopoulos A, Bravou V, Peroukides S et al. Bone regulatory factors NFATc1 and Osterix in human calcific aortic valves. Int J Cardiol 2010; 139: 142-149.
14. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122: 787-795.
15. Liu YC, Zou XB, Chai YF, et al. Macrophage polarization in inflammatory diseases. Int J Biol Sci 2014; 10: 520-529.
16. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and re­modelling. J Pathol 2013; 229: 176-185.
17. Li XF, Wang Y, Zheng DD, et al. M1 macrophages pro­mote aortic valve calcification mediated by microRNA-214/ TWIST1 pathway in valvular interstitial cells. Am J Transl Res 2016; 8: 5773-5783.
18. Yanai H, Ban T, Wang Z, et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 2009; 462: 99-103.
19. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin pro­tein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191-195.
20. Sirois CM, Jin T, Miller AL, et al. RAGE is a nucleic acid recep­tor that promotes inflammatory responses to DNA. J Exp Med 2013; 210: 2447-2463.
21. Tian J, Avalos AM, Mao SY, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 2007; 8: 487-496.
22. Tian S, Zhang L, Tang J, Sica A, Locati M. HMGB1 exacer­bates renal tubulointerstitial fibrosis through facilitating M1 macrophage phenotype at the early stage of obstructive injury. Am J Physiol Renal Physiol 2015; 308: F69-75.
23. Li X, Yue Y, Zhu Y, Xiong S. Extracellular, but not intracellu­lar HMGB1, facilitates self-DNA induced macrophage activa­tion via promoting DNA accumulation in endosomes and con­tributes to the pathogenesis of lupus nephritis. Mol Immunol 2015; 65: 177-188
24. Gong W, Zheng Y, Chao F, et al. The anti-inflammatory activ­ity of HMGB1 A box is enhanced when fused with C-terminal acidic tail. J Biomed Biotechnol 2010; 2010: 915234.
25. Son M, Porat A, He M, et al. C1q and HMGB1 reciprocally regulate human macrophage polarization. Blood 2016; 128: 2218-2228.
26. Shiau DJ, Kuo WT, Davuluri GVN, et al. Hepatocellular car­cinoma-derived high mobility group box 1 triggers M2 macro­phage polarization via a TLR2/NOX2/autophagy axis. Sci Rep 2020; 10: 13582.
27. Li B, Song TN, Wang FR, et al. Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma pro­gression through inducing PD1(+) TAM expansion. Onco­genesis 2019; 8: 17.
28. Rojas A, Delgado-López F, Perez-Castro R, et al. HMGB1 enhanc­es the protumoral activities of M2 macrophages by a RAGE-de­pendent mechanism. Tumour Biol 2016; 37: 3321-3329.
29. Zhao D, Qiang JI, Zhu S, et al. Decreased serum HMGB1 associated with M2 macrophage polarization and patients with calcific aortic valve disease. BIOCELL 2020; 44: 315-321.
30. Wang B, Li F, Zhang C, Wei G, Liao P, Dong N. High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells. J Thorac Cardiovasc Surg 2016; 151: 255-262.
31. Ouyang W, O'Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity 2019; 50: 871-891.
32. Katholnig K, Linke M, Pham H, Hengstschläger M, Weich­hart T. Immune responses of macrophages and dendritic cells regulated by mTOR signalling. Biochem Soc Trans 2013; 41: 927-933.
33. Cheekatla SS, Aggarwal A, Naik S. mTOR signaling pathway regulates the IL-12/IL-10 axis in Leishmania donovani infec­tion. Med Microbiol Immunol 2012; 201: 37-46.
34. Zhu YP, Brown JR, Sag D, Zhang L, Suttles J. Adenos­ine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in mac­rophages. J Immunol 2015; 194: 584-594.
35. Shi J, Wang H, Guan H, et al. IL10 inhibits starvation-in­duced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR path­ways. Cell Death Dis 2016; 7: e2133.
36. Frauscher B, Kirsch AH, Schabhuttl C, et al. Autophagy Pro­tects From Uremic Vascular Media Calcification. Front Immu­nol 2018; 9: 1866.
37. Phadwal K, Tan X, Koo E, Zhu D, MacRae VE. Metformin ameliorates valve interstitial cell calcification by promoting au­tophagic flux. Sci Rep 2023; 13: 21435.
38. Pottoo FH, Salahuddin M, Khan FA, et al. Therapeutic en­hancing potential of piracetam with diethylstilbestrol in pre­vention of grand-mal seizures in rats: inhibition of PI3K/Akt/ mTOR signaling pathway and IL-1b, IL-6, TNF-a cytokines levels. Eur Rev Med Pharmacol Sci 2023; 27: 4735-4751.
39. Wang X, Li GJ, Hu HX, et al. Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer's disease rats. Trans Neurosci 2016; 7: 151-157.
40. Vangan N, Cao Y, Jia X, et al. mTORC1 mediates peptido­glycan induced inflammatory cytokines expression and NF-kB activation in macrophages. Microb Pathog 2016; 99: 111-118.
41. Araki Y, Gerber EE, Rajkovich KE, et al. Mouse models of SYNGAP1-related intellectual disability. PNAS 2023; 120: e2308891120.
42. Lee K, Cascella M, Marwaha R. Intellectual Disability. Stat­Pearls. [Updated 2023 Jun 4]. In: StatPearls [Internet]. Stat­Pearls Publishing, Treasure Island (FL) 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK547654/2024.
43. Montezano AC, Touyz RM. Mammalian target of rapamycin: a novel pathway in vascular calcification. Can J Cardiol 2014; 30: 482-484.
44. Hallowell RW, Collins SL, Craig JM, et al. mTORC2 signal­ling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis. Nat Commun 2017; 8: 14208.
45. Rocher C, Singla DK. SMAD-PI3K-Akt-mTOR pathway me­diates BMP-7 polarization of monocytes into M2 macrophages. PLoS One 2013; 8: e84009.
46. Weichhart T, Hengstschläger M, Linke M. Regulation of in­nate immune cell function by mTOR. Nat Rev Immunol 2015; 15: 599-614.
47. Mercalli A, Calavita I, Dugnani E, et al. Rapamycin unbalanc­es the polarization of human macrophages to M1. Immunolo­gy 2013; 140: 179-190.
48. Ohtani M, Hoshii T, Fujii H, Koyasu S, Hirao A, Matsuda S. Cutting edge: mTORC1 in intestinal CD11c+ CD11b+ den­dritic cells regulates intestinal homeostasis by promoting IL-10 production. J Immunol 2012; 188: 4736-4740.
49. Li Q, Cheng H, Liu Y, Wang X, He F, Tang L. Activation of mTORC1 by LSECtin in macrophages directs intestinal repair in inflammatory bowel disease. Cell Death Dis 2020; 11: 918.
50. Chun Y, Kim J. Autophagy: An Essential Degradation Pro­gram for Cellular Homeostasis and Life. Cells 2018; 7: 278.
51. Gomez-Virgilio L, Silva-Lucero MD, Flores-Morelos DS, et al. Autophagy: A Key Regulator of Homeostasis and Disease: An Overview of Molecular Mechanisms and Modulators. Cells 2022; 11: 2262.
52. Zhang X, Chen J, Meng Q, et al. The protective effects of long non-coding RNA-ANCR on arterial calcification. J Bone Min­er Metab 2020; 38: 421-431.
53. Dai XY, Zhao MM, Cai Y, et al. Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle re­lease. Kidney Int 2013; 83: 1042-1051.
54. Peng YQ, Xiong D, Lin X, et al. Oestrogen Inhibits Arterial Calcification by Promoting Autophagy. Sci Rep 2017; 7: 3549.
55. Neutel CHG, Hendrickx JO, Martinet W, De Meyer GRY, Guns PJ. The Protective Effects of the Autophagic and Lyso­somal Machinery in Vascular and Valvular Calcification: A Sys­tematic Review. Int J Mol Sci 2020; 21.
56. Zhou X, Xu SN, Yuan ST, et al. Multiple functions of autoph­agy in vascular calcification. Cell Biosci 2021; 11: 159.
57. Kwak MSSJ. Current Understanding of HMGB1-mediated Autophagy. J Bacteriol Virol 2013; 43: 148-154.
58. Woodman AC, Mawdsley HP, Hauser-Cram P. Parenting stress and child behavior problems within families of children with developmental disabilities: Transactional relations across 15 years. Res Dev Disabil 2015; 36: 264-276.
59. Komori T. Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2. Int J Mol Sci 2019; 20: 1694.
60. Komori T. Runx2, an inducer of osteoblast and chondrocyte differentiation. Histochem Cell Biol 2018; 149: 313-323.
61. Zurick KM, Qin C, Bernards MT. Mineralization induction ef­fects of osteopontin, bone sialoprotein, and dentin phosphopro­tein on a biomimetic collagen substrate. J Biomed Mater Res A 2013; 101: 1571-1581.
62. Dodds RA, Connor JR, James IE, et al. Human osteoclasts, not osteoblasts, deposit osteopontin onto resorption surfaces: an in vitro and ex vivo study of remodeling bone. J Bone Miner Res 1995; 10: 1666-1680.
63. Ervin DA, Merrick J. Intellectual and developmental disabili­ty: healthcare financing. Front Public Health 2014; 2: 160.
64. Shao H, Wu R, Cao L, Gu H, Chai F. Trelagliptin stimulates osteoblastic differentiation by increasing runt-related tran­scription factor 2 (RUNX2): a therapeutic implication in oste­oporosis. Bioengineered 2021; 12: 960-968.
Copyright: © 2025 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Termedia
About us Contact
Copyright notice Privacy policy Advertising policy Contact us
Quick links
Journals Books eBooks Events
© 2025 Termedia Sp. z o.o.
Developed by Bentus.