• NENG FISHERI KURNIATI Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia.
  • HUBBI NASHRULLAH MUHAMMAD Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia.
  • GAYUK KALIH PRASESTI Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia.



Atherosclerosis, Macrophage, Biomarker, Therapy targets, Systematic review


Macrophages are known to play an important role in the initiation and progression of atherosclerosis; however, the molecular signaling pathways in macrophages that are responsible for plaque rupture have not been fully identified. This study aims to identify biomarkers and therapy targets in macrophages in atherosclerotic conditions by systematic review. Research procedure of systematic reviews using the PRISMA protocol. The search engine used in this study is PubMed, with the keywords ([macrophage] AND atherosclerosis) AND (signaling pathway OR signaling pathway), the reference application used is Zotero to screen clinical articles. There were 689 articles identified and 11 clinical articles in inclusion criteria were obtained. The identification resulted in 30 biomarkers associated with macrophages in atherosclerotic conditions. The proposed biomarkers of atherosclerosis are interleukin (IL)-1β and IL-18. The proposed potential therapy targets for atherosclerosis are LOX-1 and schematic images of biomarkers in atherosclerotic plaques.


LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod Med 1986;31:906-12.

Frostegård J. Immunity, atherosclerosis and cardiovascular disease. BMC Med 2013;11:117.

Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H. Atherosclerosis: Process, indicators, risk factors and new hopes. Int J Prev Med 2014;5:927-46.

Lahoz C, Mostaza JM. Atherosclerosis as a systemic disease. Rev Esp Cardiol 2007;60:184-95.

Fisher M, Iadecola C, Sacco R. Stroke caused by atherosclerosis of the major intracranial arteries. Circ Res 2017;120:502-13.

Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: A large worldwide burden but a relatively neglected frontier. Stroke 2008;39:2396-9.

Hong YM. Atherosclerotic cardiovascular disease beginning in childhood. Korean Circ J 2010;40:1.

Khesroh AA, Al-Roumi F, Al-Zakwani I, Attur S, Rashed W, Zubaid M. Gender differences among patients with acute coronary syndrome in the Middle East. Heart Views 2017;18:77-82.

Davis NE. Atherosclerosis an inflammatory process. J Insur Med 2005;37:72-5.

Spirig R, Tsui J, Shaw S. The emerging role of TLR and innate immunity in cardiovascular disease. Cardiol Res Pract 2012;2012:181394.

Conti P, Shaik-Dasthagirisaeb Y. Atherosclerosis: A chronic inflammatory disease mediated by mast cells. Cent Eur J Immunol 2015;40:380-6.

Yamaguchi R, Yamamoto T, Sakamoto A, Ishimaru Y, Narahara S, Sugiuchi H, et al. Roles of myeloperoxidase and GAPDH in interferon-gamma production of GM-CSF-dependent macrophages. Heliyon 2016;2:e00080.

O’neal RM, Still WJ. Pathogenesis of atherosclerosis. Fed Proc 1962;21:12-4.

Zhong Y, Wang X, Ji Q, Mao X, Tang H, Yi G, et al. CD4+ LAP + and CD4 +CD25 +Foxp3 +regulatory T cells induced by nasal oxidized low-density lipoprotein suppress effector T cells response and attenuate atherosclerosis in ApoE-/-mice. J Clin Immunol 2012;32:1104-17.

Gerrity RG, Naito HK. Ultrastructural identification of monocyte-derived foam cells in fatty streak lesions. Artery 1980;8:208-14.

Abdolmaleki F, Hayat SM, Bianconi V, Johnston TP, Sahebkar A. Atherosclerosis and immunity: A perspective. Trends Cardiovasc Med 2019;29:363-71.

Tabas I, Lichtman AH. Monocyte-macrophages and T cells in atherosclerosis. Immunity 2017;47:621-34.

Hansson GK. Immune mechanisms in atherosclerosis. Arteriosclerosis Thromb Vasc Biol 2001;21:1876-90.

Zhou X, Hansson G. Detection of B cells and proinflammatory cytokines in atherosclerotic plaques of hypercholesterolaemic apolipoprotein E knockout mice. Scand J Immunol 1999;50:25-30.

Zhang C, Zhu R, Wang H, Tao Q, Lin X, Ge S, et al. Nicotinamide phosphate transferase (NAMPT) increases in plasma in patients with acute coronary syndromes, and promotes macrophages to M2 polarization. Int Heart J 2018;59:1116-22.

Hirayama D, Iida T, Nakase H. The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci 2017;19:92.

Kumar V. Macrophages: The potent immunoregulatory innate immune cells. In: Macrophage Activation Biology and Disease. London: IntechOpen; 2019.

Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol 2018;14:49.

Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol 2008;181:5829-35.

Hilhorst M, Shirai T, Berry G, Goronzy JJ, Weyand CM. T cell-macrophage interactions and granuloma formation in vasculitis. Front Immunol 2014;5:432.

Dahl TB, Yndestad A, Skjelland M, Øie E, Dahl A, Michelsen A, et al. Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: Possible role in inflammation and plaque destabilization. Circulation 2007;115:972-80.

Françoso LA, Coates V. Anatomicopathological evidence of the beginning of atherosclerosis in infancy and adolescence. Arq Bras Cardiol 2002;78:137-42.

Griffin BA. Lipoprotein atherogenicity: An overview of current mechanisms. Proc Nutr Soc 1999;58:163-9.

Duprez DA, Cohn JN. Detection of early cardiovascular disease. In: Willerson JT, Wellens HJ, Cohn JN, Holmes DR, editors. Cardiovascular Medicine. London: Springer; 2007. p. 1615-22.

Charo IF, Taub R. Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nat Rev Drug Discov 2011;10:365-76.

Moore KJ, Tabas I. The cellular biology of macrophages in atherosclerosis. Cell 2011;145:341-55.

Gui T, Shimokado A, Sun Y, Akasaka T, Muragaki Y. Diverse roles of macrophages in atherosclerosis: From inflammatory biology to biomarker discovery. Mediators Inflamm 2012;2012:e693083.

Zhai C, Cheng J, Mujahid H, Wang H, Kong J, Yin Y, et al. Selective inhibition of PI3K/Akt/mTOR signaling pathway regulates autophagy of macrophage and vulnerability of atherosclerotic plaque. PLoS One 2014;9:e90563.

Ng MK, Quinn CM, McCrohon JA, Nakhla S, Jessup W, Handelsman DJ, et al. Androgens up-regulate atherosclerosis-related genes in macrophages from males but not females: Molecular insights into gender differences in atherosclerosis. J Am Coll Cardiol 2003;42:1306-13.

Shi X, Xie WL, Kong WW, Chen D, Qu P. Expression of the NLRP3 inflammasome in carotid atherosclerosis. J Stroke Cerebrovasc Dis 2015;24:2455-66.

Dunaeva M, Voo S, van Oosterhoud C, Waltenberger J. Sonic hedgehog is a potent chemoattractant for human monocytes: Diabetes mellitus inhibits Sonic hedgehog-induced monocyte chemotaxis. Basic Res Cardiol 2010;105:61-71.

Watanabe R, Shirai T, Namkoong H, Zhang H, Berry GJ, Wallis BB, et al. Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. J Clin Invest 2017;127:2725-38.

Li L, Sawamura T, Renier G. Glucose enhances human macrophage LOX-1 expression: Role for LOX-1 in glucose-induced macrophage foam cell formation. Circ Res 2004;94:892-901.

Lee K, Santibanez-Koref M, Polvikoski T, Birchall D, Mendelow AD, Keavney B. Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture. Atherosclerosis 2013;226:74-81.

Dorweiler B, Grechowa I, Wallrath A, Vahl CF, Horke S. Activation of the proapoptotic unfolded protein response in plaques of the human carotid artery. Eur J Vasc Endovasc Surg 2014;48:248-57.

Peltonen T, Näpänkangas J, Vuolteenaho O, Ohtonen P, Soini Y, Juvonen T, et al. Apelin and its receptor APJ in human aortic valve stenosis. J Heart Valve Dis 2009;18:644-52.

Kang JG, Sung HJ, Jawed SI, Brenneman CL, Rao YN, Sher S, et al. FOS expression in blood as a LDL-independent marker of statin treatment. Atherosclerosis 2010;212:567-70.

Li J, Chen H, Ren J, Song J, Zhang F, Zhang J, et al. Effects of statin on circulating microRNAome and predicted function regulatory network in patients with unstable angina. BMC Med Genomics 2015;8:12.

Bäck M, Hansson G. Basic mechanisms of atherosclerosis. In: Chronic Coronary Artery Disease. Amsterdam, Netherlands: Elsevier; 2018. p. 45-54.

Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: From pathophysiology to practice. J Am Coll Cardiol 2009;54:2129-38.

Barbalho SM, Bechara MD, Quesada K, Gabaldi MR, de Goulart RA, Tofano RJ, et al. Metabolic syndrome, atherosclerosis and inflammation: An inseparable triad? J Vasc Bras 2015;14:319-27.

Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 2009;27:165-97.

Paoletti R, Bolego C, Poli A, Cignarella A. Metabolic syndrome, inflammation and atherosclerosis. Vasc Health Risk Manag 2006;2:145-52.

Wolf D, Stachon P, Bode C, Zirlik A. Inflammatory mechanisms in atherosclerosis. Hamostaseologie 2014;34:63-71.

Moore K, Sheedy F, Fisher E. Macrophages in atherosclerosis: A dynamic balance. Nat Rev Immunol 2013;13:709-21.

Turner C, Devitt A, Parker K, MacFarlane M, Giuliano M, Cohen G, et al. Macrophage-mediated clearance of cells undergoing caspase-3- independent death. Cell Death Differ 2003;10:302-12.

Gonzalez L, Trigatti BL. Macrophage apoptosis and necrotic core development in atherosclerosis: A rapidly advancing field with clinical relevance to imaging and therapy. Can J Cardiol 2017;33:303-12.

Martinet W, Verheye S, De Meyer GR. Selective Depletion of macrophages in atherosclerotic plaques via macrophage-specific initiation of cell death. Trends Cardiovasc Med 2007;17:69-75.

Razavian M, Tavakoli S, Zhang J, Nie L, Dobrucki LW, Sinusas AJ, et al. Atherosclerosis plaque heterogeneity and response to therapy detected by in vivo molecular imaging of matrix metalloproteinase activation. J Nucl Med 2011;52:1795-802.

Wågsäter D, Zhu C, Björkegren J, Skogsberg J, Eriksson P. MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the Ldlr(-/-)Apob(100/100) mouse. Int J Mol Med 2011;28:247-53.

Mannarino E, Pirro M. Molecular biology of atherosclerosis. Clin Cases Miner Bone Metab 2008;5:57-62.

Hopkins PN. Molecular biology of atherosclerosis. Physiol Rev 2013;93:1317-542.

Alfarisi HA, Mohamed ZB, Ibrahim MB. Basic pathogenic mechanisms of atherosclerosis. Egypt J Basic Appl Sci 2020;7:116-25.

Zhang X, Li J, Qin JJ, Cheng WL, Zhu X, Gong FH, et al. Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/ STAT3 signaling in macrophages. J Lipid Res 2017;58:895-906.

Zhang J, Zu Y, Dhanasekara CS, Li J, Wu D, Fan Z, et al. Detection and treatment of atherosclerosis using nanoparticles: Detection and treatment of atherosclerosis using nanoparticles. WIREs Nanomed Nanobiotechnol 2017;9:e1412.

Jamkhande PG, Chandak PG, Dhawale SC, Barde SR, Tidke PS, Sakhare RS. Therapeutic approaches to drug targets in atherosclerosis. Saudi Pharm J 2014;22:179-90.

Rashid I, Maghzal GJ, Chen YC, Cheng D, Talib J, Newington D, et al. Myeloperoxidase is a potential molecular imaging and therapeutic target for the identification and stabilization of high-risk atherosclerotic plaque. Eur Heart J 2018;39:3301-10.

Adameova A, Xu YJ, Duhamel TA, Tappia PS, Shan L, Dhalla NS. Anti-atherosclerotic molecules targeting oxidative stress and inflammation. Curr Pharm Des 2009;15:3094-107.

Wickline SA, Neubauer AM, Winter PM, Caruthers SD, Lanza GM. Molecular imaging and therapy of atherosclerosis with targeted nanoparticles. J Magn Reson Imaging 2007;25:667-80.

Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, et al. Lack of interleukin-1β decreases the severity of atherosclerosis in apoE-deficient mice. Arterioscler Thromb Vasc Biol 2003;23:656-60.

Bhaskar V, Yin J, Mirza AM, Phan D, Vanegas S, Issafras H, et al. Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in apolipoprotein E-deficient mice. Atherosclerosis 2011;216:313-20.

Viana-Huete V, Fuster JJ. Potential therapeutic value of interleukin 1b-targeted strategies in atherosclerotic cardiovascular disease. Rev Esp Cardiol 2019;72:760-6.

Sterpetti AV. Inflammatory cytokines and atherosclerotic plaque progression. therapeutic implications. Curr Atheroscler Rep 2020;22:75.

Mai W, Liao Y. Targeting IL-1β in the treatment of atherosclerosis. Front Immunol 2020;11:589654.

Khan R, Rheaume E, Tardif JC. Examining the role of and treatment directed at IL-1β in atherosclerosis. Curr Atheroscler Rep 2018;20:53.

Moriya J. Critical roles of inflammation in atherosclerosis. J Cardiol 2019;73:22-7.

Chamberlain J, Evans D, King A, Dewberry R, Dower S, Crossman D, et al. Interleukin-1beta and signaling of interleukin-1 in vascular wall and circulating cells modulates the extent of neointima formation in mice. Am J Pathol 2006;168:1396-403.

Kamari Y, Werman-Venkert R, Shaish A, Werman A, Harari A, Gonen A, et al. Differential role and tissue specificity of interleukin-1alpha gene expression in atherogenesis and lipid metabolism. Atherosclerosis 2007;195:31-8.

Englesbe MJ, Deou J, Bourns BD, Clowes AW, Daum G. Interleukin-1β inhibits PDGF-BB-induced migration by cooperating with PDGF-BB to induce cyclooxygenase-2 expression in baboon aortic smooth muscle cells. J Vasc Surg 2004;39:1091-6.

Wang X, Feuerstein GZ, Gu JL, Lysko PG, Yue TL. Interleukin-1 beta induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. Atherosclerosis 1995;115:89-98.

Galea J, Armstrong J, Gadsdon P, Holden H, Francis SE, Holt CM. Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol 1996;16:1000-6.

Roell MK, Issafras H, Bauer RJ, Michelson KS, Mendoza N, Vanegas SI, et al. Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity. J Biol Chem 2010;285:20607-14.

Owyang AM, Issafras H, Corbin J, Ahluwalia K, Larsen P, Pongo E, et al. XOMA 052, a potent, high-affinity monoclonal antibody for the treatment of IL-1β-mediated diseases. MAbs 2011;3:49-60.

Whitman SC, Ravisankar P, Daugherty A. Interleukin-18 enhances atherosclerosis in apolipoprotein E-/-mice through release of interferon-γ. Circ Res 2002;90:E34-8.

Bhat OM, Kumar PU, Giridharan NV, Kaul D, Kumar MJ, Dhawan V. Interleukin-18-induced atherosclerosis involves CD36 and NF-κB crosstalk in Apo E-/-mice. J Cardiol 2015;66:28-35.

Yamaoka-Tojo M, Tojo T, Wakaume K, Kameda R, Nemoto S, Takahira N, et al. Circulating interleukin-18: A specific biomarker for atherosclerosis-prone patients with metabolic syndrome. Nutr Metab 2011;8:3.

Wang J, Sun C, Gerdes N, Liu C, Liao M, Liu J, et al. Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Nat Med 2015;21:820-6.

Badimon L. Interleukin-18: A potent pro-inflammatory cytokine in atherosclerosis: Expert’s perspective. Cardiovasc Res 2012;96:172-5.

Jefferis BJ, Papacosta O, Owen CG, Wannamethee SG, Humphries SE, Woodward M, et al. Interleukin 18 and coronary heart disease: Prospective study and systematic review. Atherosclerosis 2011;217:227-33.

Elhage R, Jawien J, Rudling M, Ljunggren HG, Takeda K, Akira S, et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc Res 2003;59:234-40.

Tang X. Analysis of interleukin 17 and interleukin 18 levels in animal models of atherosclerosis. Exp Ther Med 2019;18:517-22.

Munckhof IV, ter Horst R, Schraa K, Stienstra R, de Graaf J, Riksen N, et al. Il-18 Binding protein: A novel biomarker in obesity-related atherosclerosis that modulates lipoprotein metabolism. Atherosclerosis 2019;287:e75.

Formanowicz D, Gutowska K, Formanowicz P. Theoretical studies on the engagement of interleukin 18 in the immuno-inflammatory processes underlying atherosclerosis. Int J Mol Sci 2018;19:3476.

Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, et al. Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with Type 2 diabetes. Diabetes Care 2005;28:2890-5.

Hernesniemi JA, Heikkilä A, Raitakari OT, Kähönen M, Juonala M, Hutri-Kähönen N, et al. Interleukin-18 gene polymorphism and markers of subclinical atherosclerosis. The cardiovascular risk in young finns study. Ann Med 2010;42:223-30.

Sadeghi M, Gheraati M, Soleimani A, Amirpour A, Taheri M, Yazdekhasti S, et al. Serum interleukin-18 and extent of coronary artery disease in unstable angina. ARYA Atheroscler 2018;14:122-7.

Scherr C, de Albuquerque DC, Pozzan R, Ataide K, Ludmila T, Blanco F, et al. Role of interleukin-18 and the thrombus precursor protein in coronary artery disease. Arq Bras Cardiol 2020;114:692-8.

Autieri MV. Pro-and anti-inflammatory cytokine networks in atherosclerosis. ISRN Vasc Med 2012;2012:e987629.

Ranjbaran H, Sokol SI, Gallo A, Eid RE, Iakimov AO, D’Alessio A, et al. An inflammatory pathway of IFN-γ production in coronary atherosclerosis. J Immunol 2007;178:592-604.

Harvey E, Ramji D. Interferon-γ and atherosclerosis: Pro-or anti-atherogenic? Cardiovasc Res 2005;67:11-20.

Xu S, Liu Z, Huang Y, Le K, Tang F, Huang H, et al. Tanshinone II-A inhibits oxidized LDL-induced LOX-1 expression in macrophages by reducing intracellular superoxide radical generation and NF-κB activation. Transl Res 2012;160:114-24.

Jin P, Cong S. LOX-1 and atherosclerotic-related diseases. Clin Chim Acta 2019;491:24-9.

Pothineni NV, Karathanasis SK, Ding Z, Arulandu A, Varughese KI, Mehta JL. LOX-1 in atherosclerosis and myocardial ischemia: Biology, genetics, and modulation. J Am Coll Cardiol 2017;69:2759-68.

Henning M. LOX-1 and atherosclerosis. Circ Res 2007;100:1534-6.

Tian K, Ogura S, Little PJ, Xu SW, Sawamura T. Targeting LOX-1 in atherosclerosis and vasculopathy: Current knowledge and future perspectives. Ann N Y Acad Sci 2019;1443:34-53.

Pirillo A, Norata GD, Catapano AL. LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm 2013;2013:e152786.

Mehta JL, Chen J, Hermonat PL, Romeo F, Novelli G. Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): A critical player in the development of atherosclerosis and related disorders. Cardiovasc Res 2006;69:36-45.

World Health Organization. Data About Cardiovascular Diseases in the World. Geneva: World Health Organization; 2019. Available from: [Last accessed on 2019 Dec 16].

Abbas AK. Basic Immunology: Functions and Disorders of the Immune System. 5th ed. Singapore: Elsevier; 2016.



How to Cite

KURNIATI, N. F., H. N. MUHAMMAD, and G. K. PRASESTI. “BIOMARKERS IDENTIFICATION AND THERAPY TARGET IN MACROPHAGE OF ATHEROSCLEROSIS: SYSTEMATIC REVIEW”. Asian Journal of Pharmaceutical and Clinical Research, vol. 14, no. 3, Mar. 2021, pp. 30-39, doi:10.22159/ajpcr.2021.v14i3.40336.



Review Article(s)

Most read articles by the same author(s)