The Inflammatory Basis of Atherosclerosis: Current Understanding and Future Therapeutic Directions
Article Sidebar
Page Numbers:
1374-1392
Digital Object Identifier:
10.58578/mikailalsys.v4i2.9206
Viewed: 50 times
Downloaded: 37 times
LYAS Publisher cordially invites qualified professionals to serve as Editors or Reviewers. Your expertise will make an important contribution to maintaining and strengthening the academic quality of our publications. Interested applicants are kindly requested to complete the application form at the following link: Editors & Reviewers
Please feel free to contact us if you need any further information about the submission process or if you have any additional questions.
Authors:Asezebhobor Eseosa1*, Aluyor Abraham2
Copyright :Authors retain copyright and grant the journal right of first publication.
Main Article Content
Abstract
Although atherosclerosis has increasingly been recognized as a chronic inflammatory disease, comprehensive reviews that integrate the inflammatory mechanisms underlying atherosclerotic progression remain limited. This review aims to synthesize current knowledge on inflammation-driven pathways in atherosclerotic lesion development and evaluate the clinical relevance of targeting these pathways. A narrative review approach was employed through examination of experimental studies, pathological evidence, and clinical trials identified from PubMed, Scopus, Web of Science, and Google Scholar, with literature selected based on its relevance to inflammatory mechanisms in atherosclerosis. The findings indicate that endothelial inflammatory responses initiate lesion development by promoting immune cell infiltration into the vessel wall, while persistent immune activity accelerates plaque growth and disease progression. Clinical evidence further shows that targeted anti-inflammatory therapies, particularly IL-1β inhibition and colchicine, can significantly reduce cardiovascular events, although therapeutic responses vary across patient populations. These findings support the evolving paradigm of atherosclerosis as an immune-mediated disease and clarify the interplay between inflammation, lipid metabolism, and vascular pathology. The review concludes that inflammation represents a central and therapeutically relevant mechanism in atherosclerosis. Its contribution lies in advancing cardiovascular immunology literature while offering practical implications for clinicians and policymakers to prioritize inflammation assessment and consider anti-inflammatory strategies in high-risk populations. Future research should further examine context-specific inflammatory phenotypes, optimal intervention timing, plaque-specific biomarkers, and the integration of anti-inflammatory approaches with existing cardiovascular therapies.
Citation Metrics:
Downloads
Article Details
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
References
Ahmed, M., Hashmi, T. M., Shafiq, A., Ashraf, H., Jain, H., Khanji, M. Y., Providência, R., Chahal, A. A., Rana, J. S., Farhan, M., Ahmed, R., Fudim, M., & Fonarow, G. C. (2025). Efficacy and safety of colchicine in patients with coronary artery disease: An updated meta-analysis of randomized controlled trials. American Heart Journal Plus: Cardiology Research and Practice, 59, Article 100610. https://doi.org/10.1016/j.ahjo.2025.100610
Ajoolabady, A., Pratico, D., Lin, L., Mantzoros, C. S., Bahijri, S., Tuomilehto, J., & Ren, J. (2024). Inflammation in atherosclerosis: Pathophysiology and mechanisms. Cell Death & Disease, 15(11), Article 817. https://doi.org/10.1038/s41419-024-07166-8
Baker, R. G., Hayden, M. S., & Ghosh, S. (2011). NF-κB, inflammation, and metabolic disease. Cell Metabolism, 13(1), 11–22. https://doi.org/10.1016/j.cmet.2010.12.008
Balsinde, J., Winstead, M. V., & Dennis, E. A. (2002). Phospholipase A2 regulation of arachidonic acid mobilization. FEBS Letters, 531(1), 2–6. https://doi.org/10.1016/S0014-5793(02)03413-0
Blake, G. J., & Ridker, P. M. (2000). Are statins anti-inflammatory? Current Controlled Trials in Cardiovascular Medicine, 1(3), 161–165. https://doi.org/10.1186/cvm-1-3-161
Chávez-Sánchez, L., Madrid-Miller, A., Chávez-Rueda, K., Legorreta-Haquet, M. V., Tesoro-Cruz, E., & Blanco-Favela, F. (2010). Activation of TLR2 and TLR4 by minimally modified low-density lipoprotein in human macrophages and monocytes triggers the inflammatory response. Human Immunology, 71(8), 737–744. https://doi.org/10.1016/j.humimm.2010.05.005
Cominacini, L., Fratta Pasini, A., Garbin, U., Davoli, A., Tosetti, M. L., Campagnola, M., Rigoni, A., Pastorino, A. M., Lo Cascio, V., & Sawamura, T. (2000). Oxidized low-density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-κB through an increased production of intracellular reactive oxygen species. Journal of Biological Chemistry, 275(17), 12633–12638. https://doi.org/10.1074/jbc.275.17.12633
Cyr, A. R., Huckaby, L. V., Shiva, S. S., & Zuckerbraun, B. S. (2020). Nitric oxide and endothelial dysfunction. Critical Care Clinics, 36(2), 307–321. https://doi.org/10.1016/j.ccc.2019.12.009
Feng, B., Yao, P. M., Li, Y., Devlin, C. M., Zhang, D., Harding, H. P., Sweeney, M., Rong, J. X., Kuriakose, G., Fisher, E. A., Marks, A. R., Ron, D., & Tabas, I. (2003). The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nature Cell Biology, 5(9), 781–792. https://doi.org/10.1038/ncb1035
Funk, C. D. (2001). Prostaglandins and leukotrienes: Advances in eicosanoid biology. Science, 294(5548), 1871–1875. https://doi.org/10.1126/science.294.5548.1871
Gimbrone, M. A., Jr., & García-Cardeña, G. (2016). Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circulation Research, 118(4), 620–636. https://doi.org/10.1161/CIRCRESAHA.115.306301
Hansson, G. K., & Hermansson, A. (2011). The immune system in atherosclerosis. Nature Immunology, 12(3), 204–212. https://doi.org/10.1038/ni.2001
Hansson, G. K., Robertson, A.-K. L., & Söderberg-Nauclér, C. (2006). Inflammation and atherosclerosis. Annual Review of Pathology: Mechanisms of Disease, 1, 297–329. https://doi.org/10.1146/annurev.pathol.1.110304.100100
Harrington, R. A. (2017). Targeting inflammation in coronary artery disease. New England Journal of Medicine, 377(12), 1197–1198. https://doi.org/10.1056/NEJMe1709904
Huang, Y., Wang, Y., Wang, Y., Yi, S., Fan, Z., Sun, L., & Dou, G. (2014). Role of macrophage matrix metalloproteinase expression in plaque vulnerability. International Journal of Molecular Medicine, 34(2), 456–464. https://doi.org/10.3892/ijmm.2014.1646
Imazio, M. (2024). Colchicine for the treatment of the spectrum of atherosclerotic events: Clinical evidence. Journal of Cardiovascular Medicine, 25(9), 653–663. https://doi.org/10.2459/JCM.0000000000001647
Jiang, H., Zhou, Y., Nabavi, S. M., Sahebkar, A., Little, P. J., Xu, S., Weng, J., & Ge, J. (2022). Mechanisms of oxidized LDL-mediated endothelial dysfunction and its consequences for the development of atherosclerosis. Frontiers in Cardiovascular Medicine, 9, Article 925923. https://doi.org/10.3389/fcvm.2022.925923
Kawai, T., & Akira, S. (2007). Signaling to NF-κB by Toll-like receptors. Trends in Molecular Medicine, 13(11), 460–469. https://doi.org/10.1016/j.molmed.2007.09.002
Khan, M. S., Talha, K. M., Maqsood, M. H., Rymer, J. A., Borlaug, B. A., Docherty, K. F., Pandey, A., Kahles, F., Cikes, M., Lam, C. S. P., Ducharme, A., Voors, A. A., Hernandez, A. F., Lincoff, A. M., Petrie, M. C., Ridker, P. M., & Fudim, M. (2024). Interleukin-6 and cardiovascular events in healthy adults: MESA. JACC: Advances, 3(8), Article 101063. https://doi.org/10.1016/j.jacadv.2024.101063
Kong, P., Cui, Z.-Y., Huang, X.-F., Zhang, D.-D., Guo, R.-J., & Han, M. (2022). Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal Transduction and Targeted Therapy, 7, Article 131. https://doi.org/10.1038/s41392-022-00955-7
Li, D., & Mehta, J. L. (2000). Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: Evidence from use of antisense LOX-1 mRNA and chemical inhibitors. Arteriosclerosis, Thrombosis, and Vascular Biology, 20(4), 1116–1122. https://doi.org/10.1161/01.ATV.20.4.1116
Li, L., Liu, S., Tan, J., Wei, L., Wu, D., Gao, S., Weng, Y., & Chen, J. (2022). Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies. Journal of Tissue Engineering, 13, Article 20417314221088509. https://doi.org/10.1177/20417314221088509
Li, Y., Schwabe, R. F., DeVries-Seimon, T., Yao, P. M., Gerbod-Giannone, M.-C., Tall, A. R., Davis, R. J., Flavell, R., Brenner, D. A., & Tabas, I. (2005). Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: Model of NF-κB- and MAP kinase-dependent inflammation in advanced atherosclerosis. Journal of Biological Chemistry, 280(23), 21763–21772. https://doi.org/10.1074/jbc.M501759200
Libby, P. (2002). Inflammation in atherosclerosis. Nature, 420, 868–874. https://doi.org/10.1038/nature01323
Libby, P. (2021). Inflammation during the life cycle of the atherosclerotic plaque. Cardiovascular Research, 117(13), 2525–2536. https://doi.org/10.1093/cvr/cvab303
Libby, P. (2021). Inflammation in atherosclerosis: Transition from theory to practice. Journal of the American College of Cardiology, 77(12), 1560–1570. https://doi.org/10.1016/j.jacc.2021.01.032
Libby, P., Tabas, I., Fredman, G., & Fisher, E. A. (2014). Inflammation and its resolution as determinants of acute coronary syndromes. Circulation Research, 114(12), 1867–1879. https://doi.org/10.1161/CIRCRESAHA.114.302699
Lin, J., Kakkar, V., & Lu, X. (2014). Impact of MCP-1 in atherosclerosis. Current Pharmaceutical Design, 20(28), 4580–4588. https://doi.org/10.2174/1381612820666140522115801
Mehta, J. L., Sanada, N., Hu, C. P., Chen, J., Dandapat, A., Sugawara, F., Satoh, H., Inoue, K., Kawase, Y., Jishage, K.-I., Suzuki, H., Takeya, M., Schnackenberg, L., Beger, R., Hermonat, P. L., Thomas, M., & Sawamura, T. (2007). Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high-cholesterol diet. Circulation Research, 100(11), 1634–1642. https://doi.org/10.1161/CIRCRESAHA.107.149724
Mehta, N. N., deGoma, E., & Shapiro, M. D. (2025). IL-6 and cardiovascular risk: A narrative review. Current Atherosclerosis Reports, 27(1), Article 12. https://doi.org/10.1007/s11883-024-01259-7
Miller, Y. I., Choi, S.-H., Wiesner, P., Fang, L., Harkewicz, R., Hartvigsen, K., Boullier, A., Gonen, A., Diehl, C. J., Que, X., Montano, E., Shaw, P. X., Tsimikas, S., Binder, C. J., & Witztum, J. L. (2011). Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circulation Research, 108(2), 235–248. https://doi.org/10.1161/CIRCRESAHA.110.223875
Nedkoff, L., Briffa, T., Zemedikun, D., Herrington, S., & Wright, F. L. (2023). Global trends in atherosclerotic cardiovascular disease. Clinical Therapeutics, 45(11), 1087–1091. https://doi.org/10.1016/j.clinthera.2023.09.020
Pirillo, A., Norata, G. D., & Catapano, A. L. (2013). LOX-1, OxLDL, and atherosclerosis. Mediators of Inflammation, 2013, Article 152786. https://doi.org/10.1155/2013/152786
Poston, R. N. (2019). Atherosclerosis: Integration of its pathogenesis as a self-perpetuating propagating inflammation: A review. Cardiovascular Endocrinology and Metabolism, 8(2), 51–61. https://doi.org/10.1097/XCE.0000000000000172
Poznyak, A. V., Nikiforov, N. G., Markin, A. M., Kashirskikh, D. A., Myasoedova, V. A., Gerasimova, E. V., & Orekhov, A. N. (2021). Overview of OxLDL and its impact on cardiovascular health: Focus on atherosclerosis. Frontiers in Pharmacology, 11, Article 613780. https://doi.org/10.3389/fphar.2020.613780
Rajendran, P., Rengarajan, T., Thangavel, J., Nishigaki, Y., Sakthisekaran, D., Sethi, G., & Nishigaki, I. (2013). The vascular endothelium and human diseases. International Journal of Biological Sciences, 9(10), 1057–1069. https://doi.org/10.7150/ijbs.7502
Ridker, P. M., Danielson, E., Fonseca, F. A. H., Genest, J., Gotto, A. M., Jr., Kastelein, J. J. P., Koenig, W., Libby, P., Lorenzatti, A. J., MacFadyen, J. G., Nordestgaard, B. G., Shepherd, J., Willerson, J. T., & Glynn, R. J. (2008). Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New England Journal of Medicine, 359(21), 2195–2207. https://doi.org/10.1056/NEJMoa0807646
Ridker, P. M., Devalaraja, M., Baeres, F. M. M., Engelmann, M. D. M., Hovingh, G. K., Ivkovic, M., Lo, L., Kling, D., Pergola, P., Raj, D., Libby, P., & Davidson, M. (2021). IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): A double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet, 397(10289), 2060–2069. https://doi.org/10.1016/S0140-6736(21)00520-1
Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., Kastelein, J. J. P., Cornel, J. H., Pais, P., Pella, D., Genest, J., Cifkova, R., Lorenzatti, A., Forster, T., Kobalava, Z., … Glynn, R. J. (2017). Antiinflammatory therapy with canakinumab for atherosclerotic disease. New England Journal of Medicine, 377(12), 1119–1131. https://doi.org/10.1056/NEJMoa1707914
Ridker, P. M., MacFadyen, J. G., Thuren, T., Everett, B. M., Libby, P., & Glynn, R. J. (2018). Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: Analyses from the CANTOS study. European Heart Journal, 39(38), 3499–3507. https://doi.org/10.1093/eurheartj/ehy389
Ridker, P. M., Rifai, N., Stampfer, M. J., & Hennekens, C. H. (2000). Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation, 101(15), 1767–1772. https://doi.org/10.1161/01.CIR.101.15.1767
Roshan, M. H. K., Tambo, A., & Pace, N. P. (2016). The role of TLR2, TLR4, and TLR9 in the pathogenesis of atherosclerosis. International Journal of Inflammation, 2016, Article 1532832. https://doi.org/10.1155/2016/1532832
Serhan, C. N., & Savill, J. (2005). Resolution of inflammation: The beginning programs the end. Nature Immunology, 6(12), 1191–1197. https://doi.org/10.1038/ni1276
Serhan, C. N., Chiang, N., & Van Dyke, T. E. (2008). Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nature Reviews Immunology, 8(5), 349–361. https://doi.org/10.1038/nri2294
Singh, B., Cui, K., Eisa-Beygi, S., Zhu, B., Cowan, D. B., Shi, J., Wang, D.-Z., Liu, Z., Bischoff, J., & Chen, H. (2024). Elucidating the crosstalk between endothelial-to-mesenchymal transition (EndoMT) and endothelial autophagy in the pathogenesis of atherosclerosis. Vascular Pharmacology, 155, Article 107368. https://doi.org/10.1016/j.vph.2024.107368
Singh, S., Anshita, D., & Ravichandiran, V. (2021). MCP-1: Function, regulation, and involvement in disease. International Immunopharmacology, 101, Article 107598. https://doi.org/10.1016/j.intimp.2021.107598
Tabas, I. (2010). The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circulation Research, 107(7), 839–850. https://doi.org/10.1161/CIRCRESAHA.110.224766
Tabas, I., & Bornfeldt, K. E. (2016). Macrophage phenotype and function in different stages of atherosclerosis. Circulation Research, 118(4), 653–667. https://doi.org/10.1161/CIRCRESAHA.115.306256
Tall, A. R., & Yvan-Charvet, L. (2015). Cholesterol, inflammation and innate immunity. Nature Reviews Immunology, 15(2), 104–116. https://doi.org/10.1038/nri3793
Tardif, J.-C., Kouz, S., Waters, D. D., Bertrand, O. F., Diaz, R., Maggioni, A. P., Pinto, F. J., Ibrahim, R., Gamra, H., Kiwan, G. S., Berry, C., López-Sendón, J., Ostadal, P., Koenig, W., Angoulvant, D., Grégoire, J. C., Lavoie, M.-A., Dubé, M.-P., Rhainds, D., … Roubille, F. (2019). Efficacy and safety of low-dose colchicine after myocardial infarction. New England Journal of Medicine, 381(26), 2497–2505. https://doi.org/10.1056/NEJMoa1912388
Timmins, J. M., Ozcan, L., Seimon, T. A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel-Duby, R., Olson, E. N., Anderson, M. E., & Tabas, I. (2009). Calcium/calmodulin-dependent protein kinase II links endoplasmic reticulum stress with Fas and mitochondrial apoptosis pathways. Journal of Clinical Investigation, 119(10), 2925–2941. https://doi.org/10.1172/JCI38857
Wang, D., & DuBois, R. N. (2010). Eicosanoids and cancer. Nature Reviews Cancer, 10(3), 181–193. https://doi.org/10.1038/nrc2809
Xu, S., Liu, Y., Zhu, M., Chen, K., Xu, F., & Liu, Y. (2025). Global burden of atherosclerotic cardiovascular disease attributed to lifestyle and metabolic risks. Science China Life Sciences, 68(9), 2739–2754. https://doi.org/10.1007/s11427-025-2948-y
Xu, Y., Zhang, Y., & Li, X. (2022). NLRP3 inflammasome and atherosclerosis: Mechanisms and potential therapeutic targets. Signal Transduction and Targeted Therapy, 7(1), Article 251. https://doi.org/10.1038/s41392-022-01099-4
Zhang, H., Lui, K. O., & Zhou, B. (2024). Elucidating the crosstalk between endothelial-to-mesenchymal transition (EndoMT) and endothelial autophagy in the pathogenesis of atherosclerosis. Pharmacological Research, 201.