Targeting inflammation in atherosclerosis: prospects and limitations



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Abstract

Despite the effective measures of hypolipidemic and hypotensive therapy as well as the correction of metabolic disorders and control of smoking, many patients still remain at risk for atherosclerosis progression, and cardiovascular diseases contitue to rank first among the leading causes of mortality. In order to address this issue, efforts are being made to influence the "residual" risk of cardiovascular events, particularly by suppressing inflammation in the vascular wall. Anti-inflammatory therapies currently being tested in clinical trials lead to a certain reduction in the risk of atherosclerosis progression and clinical manifestations. However, according to some studies, this therapy may also increase the risk of dangerous infections. Furthermore, there is a possibility that suppressing inflammation in the vessel wall could potentially slow down the removal of cholesterol, which could be considered a potential drawback of this treatment approach.
This review explores the involvement of various inflammatory factors in the development of atherosclerosis, both in the early and late stages, provides clinical evidence on the association between inflammation and atherogenesis as well as the results of anti-inflammatory therapies in preventing the development of atherosclerotic complications. Based on these findings, an analysis is conducted on the potential prospects and limitations of using anti-inflammatory medications for atherosclerosis treatment. The review also explores promising alternative approaches to influencing the immune system as a means of treating atherosclerosis and preventing its complications.

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ВВЕДЕНИЕ

The development and implementation of effective lipid and blood pressure-lowering therapies, as well as the correction of metabolic disorders and smoking cessation, have significantly improved the situation regarding the treatment and prevention of atherosclerosis and its complications. However, despite these efforts, many patients are still at risk of developing atherosclerosis and the mortality rate from cardiovascular disease remains high, accounting for the majority of deaths from various causes [1].

In this context, efforts are being made to address the "residual" risk of cardiovascular events, particularly by targeting inflammation in the vascular wall [2]. The anti-inflammatory therapies currently used in clinical trials, such as blocking antibodies to cytokines and low doses of colchicine, have been shown to lead to a slight reduction in the risk of atherosclerosis progression and the development of its clinical manifestations. However, according to some studies, these therapies may increase the risk of fatal infections [3]. Additionally, there is a possibility that suppressing the inflammatory process in the vascular wall could slow down the removal of cholesterol from it, which could be considered a disadvantage of this approach. Therefore, the goal of this review is to examine the potential benefits and limitations of using anti-inflammatory medications for treatment of atherosclerosis.

 

Inflammation and cytokines in pathogenesis of atherosclerosis

At the initial stage of atherogenesis, the transport of low-density lipoproteins (LDL) from the bloodstream to the intima occurs in large and medium-sized arteries, mainly in areas exposed to turbulent blood flow [4, 5]. After passing through the endothelial layer, LDL are trapped in the intima due to the binding of their main protein, apolipoprotein B, to glycosaminoglycans [6], and then LDL undergoe various chemical modifications (oxidation, glycation, proteolysis, etc.) [7]. Modified LDL are then taken up by macrophages, which are present in small numbers in the normal intima of the arteries, through the use of various scavenger receptors (SRA, CD36, Lox-1, etc.). The expression and activity of these receptors is largely independent of intracellular cholesterol levels. The active uptake of modified LDL by macrophages leads to the accumulation of large amounts of cholesterol and its esters in these cells [8] (These and further mechanistic steps of atherogenesis are shown in Fig. 1.). It should be noted that vascular SMCs that have migrated to intima also participate in this process [9].

Intracellular accumulation of cholesterol (in vacuoles) occurs due to the lack of enzymes in macrophages and other cells of the arterial wall that are capable of breaking down cholesterol. This cholesterol can be removed from the intima of arteries only with the participation of the reverse cholesterol transport system involving high-density lipoproteins or together with lipid-laden macrophages that leave the vascular wall [10]. The uptake of modified LDL and their interaction with macrophage pattern-recognizing receptors initiate an inflammatory response [7, 11]. In particular, the accumulation of cholesterol in macrophages leads to the activation of the NLRP3 inflammasome, which stimulates the synthesis and secretion of interleukin (IL)-1β by cells [12]. IL-1β, in turn, induces expression of its own gene in vascular endothelial and smooth muscle cells (SMC) [13, 14]. IL-1β also stimulates the expression of adhesion molecules by endothelial cells [15], and further activates the production of pro-inflammatory cytokines by macrophages, amplifying the inflammatory response [16]. IL-1β stimulates the production of IL-6 by SMC and other vascular cells as well as enhances SMC proliferation [17, 18].

Modified LDL also cause a pro-inflammatory response in endothelial cells, increasing the expression of adhesion molecules and chemokines that attract monocytes to the vascular wall [19]. Other pro-inflammatory cytokines, such as tumor necrosis factor (TNF) and IL-6, also increase the expression of adhesion molecules, E-selectin, ICAM-1 and VCAM-1 on the surface of endothelial cells [20]. TNF in the presence of another cytokine, interferon-γ (IFNγ), enhances the pro-inflammatory activation of macrophages [21, 22]. TNF and IL-6 can stimulate the migration of vascular SMC from arterial media to intima and their proliferation, as well as angiogenesis [23-26].

It is worth noting that the mentioned TNF and IL-1β cytokines stimulate the vesicular transendothelial transport of LDL to intima [27-29]. This can also contribute to further activation of atherogenesis.

Thus, the accumulation of modified LDL in the artery intima leads to the development of inflammation involving both resident intimal cells (macrophages and SMCs) and cells entering the arterial wall from the bloodstream.

During the development of inflammation, not only monocytes but also T and B lymphocytes become involved in intimal inflammation. This creates conditions for an immune response against modified LDL and the formation of antibodies that can modulate the interaction between LDL and macrophages [30, 31]. CD4+ and CD8+ T cells also play a role in regulating the inflammatory response in the arterial wall. In particular, Th1 produce IL-12, TNF, and IFNγ [32]. The latter activates macrophages and promotes the expression of scavenger receptors, leading to the foam cells formation [33]. If macrophages transfer cholesterol to the reverse transport system, in particular, to high-density lipoproteins, and/or leave the intima loading with cholesterol esters, while LDL stop entering into the vascular wall, then primary atherosclerotic lesions, such as lipid spots and stripes, will disappear [10]. If the flow of LDL into the intima exceeds the ability of macrophages to remove cholesterol from it, then developed atherosclerotic plaques (AP) will be formed, in which the inflammatory reaction progresses, a necrotic core (due to cell death), a fibrous cap and vasa vasorum are formed, and calcium is accumulated [34].

As previously mentioned, cytokines play a crucial role in inducing of SMC migration and their transformation into a synthetic phenotype, which is essential for the formation of a dense fibrous coating around atherosclerotic plaque [14, 23, 25, 26]. On the other hand, pronounced leukocyte infiltration occurring in the late stages of atherogenesis may, on the contrary, lead to the degradation of the elastic and collagenous components of the plaque through the overproduction of matrix metalloproteinases (MMPs) by mononuclear cells, as well as TNF, which at high concentrations can cause the death of SMC [22, 35-37]. Additionally, IFNγ has been shown to reduce the proliferation of SMC and their collagen production [38, 39]. Cell death, including of macrophages overloaded with cholesterol esters leads to increased inflammation, MMP production, and inhibition of collagen synthesis, all of which ultimately contribute to the rupture of AP [40]. In addition to macrophage necrosis caused by excessive accumulation of cholesterol and its esters (foam cells), cell death also occurs as a result of apoptosis caused by modified LDL or high TNF concentrations [41]. However, if efferocytosis, the process of macrophage engulfment of apoptotic cells, is not sufficiently effective in advanced atherosclerotic lesions [42], apoptosis can be replaced by secondary necrosis. This cell death results in the formation of a necrotic core in the AP, contributing to its instability.

Atherosclerosis is a chronic, unresolved inflammatory process. The cause of this chronic inflammation in AP is the accumulation of cholesterol in the intima, which, unlike other LDL components, does not undergo cleavage. Without removing excess cholesterol (as prof. I. Tabas aptly puts it, splinters), a complete resolution of the atherosclerotic process becomes impossible [43]. However, if the intake of LDL into the vascular wall is reduced, for example, by lipid-lowering therapy, the plaque becomes denser and the risk of its rupture is lower [44].

Regulatory T lymphocytes, also known as Treg cells, play an important role in aiding the repair processes in atherosclerosis. These cells produce transforming growth factor-beta (TGF-β), which stimulates collagen formation and has a profibrotic effect. Tregs also reduce the activity of T helper (Th1) and classic M1 macrophages, which are involved in inflammation and tissue damage [45, 46]. M2 macrophages, which produce IL-10 and are located around the lipid core of AP, also contribute to the healing process [47, 48]. IL-10 stimulate the processes of efferocytosis [49], which is important for removing excess cholesterol from the vascular wall during atherogenesis.

Thus, the inflammatory response occurs at all stages of atherosclerotic lesion formation and is essential for both the elimination of cholesterol from the vessel wall and the healing process when LDL intake is limited. However, the activation of mononuclear cells can lead to the release of MMP, TNF, and IFN-γ, which can contribute to plaque thinning and increase the risk of plaque rupture and atherosclerotic complications. It should be emphasized that the main negative role of inflammatory reactions in the vascular wall is due to the fact that they contribute to the destabilization of atherosclerotic plaque in humans [50] (The interplay of vascular cells during the atherosclerosis process is shown in Fig. 1).

Clinical studies on the association of inflammation with atherogenesis anti-inflammatory therapy of atherosclerosis

The results of research conducted in clinics also suggest the involvement of immune factors in the development of atherosclerosis. This is supported by evidence, such as an increased incidence of coronary heart disease (CHD) and stroke among people with rheumatoid arthritis, systemic lupus erythematosus, and other systemic autoimmune diseases [51]. It is believed that the progression of atherosclerosis in these patients is related to endothelial dysfunction, the overproduction of pro-inflammatory cytokines, and the impaired function of T and B lymphocytes [32].

In many clinical and population studies, an increased level of C-reactive protein (CRP) in the blood has been found to be a marker for the clinical manifestation of atherosclerotic cardiovascular disease (ASCVD) [52]. This also suggests that inflammation plays a role in the progression of atherosclerosis. Studies have shown that a decrease in cardiovascular events during statin medication correlates not only with lipid-lowering, but also with the anti-inflammatory effect of these drugs [53]. Even in patients who achieved low LDL cholesterol levels, plasma levels of CRP above 2 mg/L were associated with a relatively high risk of cardiovascular complications [53]. In this regard, the concept of "residual inflammatory risk" has been formed, which needs to be addressed in order to more effectively reduce the incidence of cardiovascular events [54]. Based on these clinical data and the experimental research findings mentioned above, approaches to anti-inflammatory therapy are being developed in order to reduce the progression of atherosclerosis and prevent its complications [55].

Clinical studies have shown that canakinumab, a monoclonal antibody drug that targets IL-1β, reduces the risk of CVD complications by 15-17% when administered to patients with a history of myocardial infarction and persistent inflammation (CRP levels above 2 mg/L) [3]. This drug reduces CRP and IL-6 levels in plasma, but does not affect atherogenic lipoprotein concentrations, suggesting that its cardioprotective effects are likely due to its anti-inflammatory action [3]. Another monoclonal antibody to IL-6, ziltivekimab, with strong anti-inflammatory properties, is currently tesing in clinical trials to determine its potential benefits in reducing CVD risk [56, 57]. These and other promising anti-inflammatory drugs are listed in Table 1.

Previously, several clinical studies have explored the use of colchicine at low doses to prevent complications of atherosclerosis. Colchicine, as an inhibitor of microtubule assembly in cells, has an immunosuppressive effect by reducing the activation of inflammasomes and the migration properties of leukocytes. A meta-analysis of nine clinical trials involving approximately 30,000 patients found a 12% reduction in cardiovascular events during colchicine treatment [58]. As a result, daily doses of 0.5 mg of colchicine are recommended for patients with CHD to prevent heart attacks and strokes [55, 59].

It is obvious that the undesirable effect of taking these medications can be infectious complications. For instance, taking canakinumab has led to a small but significant increase in mortality due to infections [3]. Although the above meta-analysis on the use of colchicine did not show an increase in the frequency of hospitalizations for pneumonia [58], some studies have found that the taking the drug was associated with an increase in pneumonia [60] and even with the number of deaths from non-CVD [61]. However, according to most researchers, in patients with ASCVD with an "inflammatory" risk, the benefits of anti-inflammatory therapy outweigh its potential harm. Therefore it is advisable to target the inflammatory pathways in atherogenesis, in addition to lipid-lowering therapy and other commonly used methods of treatment or prevention of atherosclerosis and its complications [55, 59]. Moreover, therapeutic approaches aimed at other targets of the inflammatory response are currently under developent: NLRP3, IL-1α, IL-18, IL-33, TNF, CD40/C40L, TRAF6, and resolvins [14, 62, 63].

Discussion: positive and negative sides of anti-inflammatory therapy of atherosclerosis

The American and European Societies of Cardiology recommend prescribing anti-inflammatory drugs, in particular colchicine 0.5 mg/day, to patients with CHD in order to reduce their risk of heart complications [55, 64]. As the above-mentioned studies have shown, anti-inflammatory therapy prevents development of atherosclerotic complications within a relatively short period of time (within a few years). This approach is most likely to be effective in cases of rapidly progressing atherosclerosis or unstable atherosclerotic plaques. In particular, using antibodies to IL-1β may be beneficial for patients with CHD in the postinfarction period, as it can help reduce the recruitment of pro-inflammatory monocytes to the infarcted area [65]. At the same time, long-term anti-inflammatory therapy, such as 10-20 years or more, is likely to contribute to the progression of atherosclerosis by suppressing of the mechanisms of cholesterol removal from the vascular wall. This is because cells of the immune system play a role in these mechanisms, as described above [10]. In addition, it is possible that the risk of prolonged infections may increase (the maximum duration of studies on the effect of anti-inflammatory drugs on the course of atherosclerosis has been up to 3.7 years [32]).

According to researchers who conduct such studies, indications for anti-inflammatory therapy in patients with atherosclerosis are signs of chronic, low-grade inflammation (inflammatory risk) that does not decrease despite measures taken to reduce atherogenesis [54]. Therefore, anti-inflammatory medications should only be included in a patient's treatment plan if their plasma CRP level is greater than 2 mg/L. However, there are several unresolved issues related to this treatment approach. Firstly, more specific markers of inflammation in atherosclerotic plaques (APs) are needed. Recent research has shown that the fat attenuation index (FAI), which reflects the lipid content of perivascular adipose tissue, could potentially serve as such a marker [66]. However, this technique requires the use of hard accessible apparatus (CT angiograph) and this approach needs to be standardized and further validated [66]. Additionally, further study of specific targets of anti-inflammatory therapy (cytokines, chemokines, adhesion molecules, M1 and M2 macrophages, Th1/Th2, Tregs, B cells, CD40/CD40L) is necessary. Finally, this approach does not negate the need to develop methods to influence underlying cause of the inflammatory process in AP, such as focal activation of LDL transport through the endothelium, LDL retention in the intima, as well as the effective removal of cholesterol from the intimal layer.

Are there alternative ways to influence the immune system to treat atherosclerosis? One possible approach is to activate the removal of apoptotic cells by macrophages in the AP. As mentioned earlier, inefficient efferocytosis is one of the causes of necrotic core formation and thinning of the plaque cap [42]. In this regard, therapies that aim to increase in the AP the concentration of factors that promote efferocytosis could be promising. This could be achieved by introducing nanoparticles containing IL-10 [67], a fragment of annexin V [68], and resolvins [69], and microRNA that inhibit the production of calcium/calmodulin-dependent protein kinase-γ (CaMKIIγ), which is an inhibitor of the pathway of MerTK synthesis, the receptor for efferocytosis [70]. During the clinical testing phase, patients with acute coronary syndrome were given low doses of IL-2 in order to increase the number of Treg cells [71]. IL-10 and TGFβ, which are produced by these Treg cells, have been shown to play a role in resolving inflammation [46].

Another possible approach to treating atherosclerosis is through the use of specific immunotherapy. In experiments on animals, administration of chemically modified LDL or fragments of apolipoprotein B led to the production of antibodies against these substances. This process was accompanied by a slowing of AP formation [72-74]. However, the mechanisms behind the protective effect and the potential for its use in humans require further study. Another potential method of immunotherapy involves introducing antibodies against specific LDL epitopes into the body to modulate its interaction with immune cells [75]. This approach aims to disrupt the process of atherosclerosis by interfering with LDL's ability to bind to and damage cells in the arterial walls.

 

Заключение

Inflammation is not a trigger of atherogenesis, but an active participant in the process. It plays a crucial role in removing excess cholesterol from the intima of the vascular wall. It is macrophages that capture LDL from the extracellular matrix and transfer cholesterol to the reverse transport system. If the flow of LDL into intima prevails over the ability of phagocytes to remove cholesterol from it, they turn into foam cells, which then die, and this leads to an increased inflammatory response and AP destabilization. Clinical studies show that anti-inflammatory therapy may slightly reduce the risk of severe atherosclerotic complications. However, the downside of this approach can be a slower removal of cholesterol from intima, as well as an increased risk of prolonged infections due to immunosuppression. Therefore, we believe that anti-inflammatory therapy should not be used for long-term. In addition, more specific markers of inflammation in AP are needed, on the basis of which indications for anti-inflammatory treatment should be determined. An alternative to this is the development of measures aimed at increasing cholesterol removal from the vascular wall, enhancing efferocytosis, and specific immunotherapy for atherosclerosis. These approaches do not, however, negate the importance of developing and implementing methods to address the underlying cause of the inflammatory response in AP, such as focal activation of transendothelial LDL transport and retention of these lipoproteins within the intima.

Table 1. Proposed anti-inflammatory drugs for the treatment of atherosclerosis

 

Group of drugs,

main representatives

Molecular target

Status of translation in clinic

Source

Anti-ILβ antibodies

(canakinumab)

ILβ

Clinical trial for ASCVD outcomes prevention is complited. The reduction in major adverse cardiovascular events is 15-17%.

[3]

Anti-IL-6 antibodies

(ziltivekimab)

IL-6

Clinical trial for ASCVD outcomes prevention is planned.

[57]

Anti-TNF antibodies, TNF inhibitors

(infliximab, etanercept)

TNF

Approved for treatment of rheumatoid arthritis. Clinical trials for ASCVD outcomes prevention are expected.

[62]

Colchicine

Microtubules and inflammasomes

 

Approved for patients with chronic CHD and after acute coronary syndrome. The mean reduction in major adverse cardiovascular events is 12%

[55, 58, 64]

Inflammasome inhibitors

Inflammasomes

Clinical trials for ASCVD outcomes prevention are expected.

[63]

CD40-CD40L inhibitors

CD40-CD40L

Experimental evidence in animals

[14]

Recombinant IL-2 (aldesleukin)

IL-2 receptors in Tregs

Clinical trial for reducing of vascular inflammation in patients with acute coronary syndrome is ongoing

[71]

Anti-oxidized LDL antibodies (orticumab)

Oxidized LDL

Clinical trials for ASCVD outcomes prevention are expected. Some evidence of decreased coronary inflammation in patients with psoriasis.

[75]

 

ASCVD - Atherosclerotic Cardiovascular Disease,  CHD - coronary heart disease, IL - interleukin, LDL - low-density lipoproteins, TNF - tumor necrosis factor, Treg - regulatory T cells

Fig. 1. The interplay of vascular cells in the atherosclerosis process. See description in main text. Abbreviations:  A - apoptotic bodies, AB - anti-lipoprotein antibodies, B - B cells, EC - endothelial cells, ECM - extracellular matrix, ICAM-1 and VCAM-1 - intercellular and vascular adhesion molecules, IL - interleukin, IFNγ - interferon-γ, FC - foam cells, H - high-density lipoproteins, L - lymphocytes, LDL - low-density lipoproteins, M1 and M2 - M1 and M2 macrophages, mLDL - modified low-density lipoproteins, MMP - matrix metalloproteinases, Mono - monocyte, NC - necrotic core, SMC - smooth muscle cell, SR - scavenger receptor, NLRP3 - NLR family pyrin domain-containing 3 inflammasome, Th - T helper cells, Th1 and Th2 - types 1 and 2 T helper cells, TNF - tumor necrosis factor, TGFβ - transforming growth factor beta, Treg - regulatory T cells.
×

About the authors

Dmitry A Tanyanskiy

ФГБНУ ИЭМ

Author for correspondence.
Email: dmitry.athero@gmail.com
ORCID iD: 0000-0002-5321-8834
SPIN-code: 9303-9445

Alexander D. Denisenko

Email: add@iem.spb.ru
ORCID iD: 0000-0003-1613-0654
SPIN-code: 7496-1449

Peter V. Pigarevsky

Email: pigarevsky@mail.ru
ORCID iD: 0000-0002-5906-6771
SPIN-code: 8636-4271

References

  1. Matskeplishvili S, Kontsevaya A. Cardiovascular Health, Disease, and Care in Russia. Circulation. 2021;144(8):586-588. doi: 10.1161/CIRCULATIONAHA.121.055239
  2. Ridker PM. Targeting residual inflammatory risk: The next frontier for atherosclerosis treatment and prevention. Vascul Pharmacol. 2023;153:107238. doi: 10.1016/j.vph.2023.107238
  3. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-1131. doi: 10.1056/NEJMoa1707914
  4. Tabas I, García-Cardeña G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol. 2015;209(1):13-22. doi: 10.1083/jcb.201412052
  5. Parfenova NS, Tanyanskiy DA. The concept of endothelial transcytosis as a theoretical prerequisite for the development of prevention and treatment of atherosclerosis. Medical Academic Journal. 2023;23(1):41-51. doi: 10.17816/MAJ321958
  6. Borén J, Olin K, Lee I, et al. Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J Clin Invest. 1998;101(12):2658-2664. doi: 10.1172/JCI2265
  7. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-2330. doi: 10.1093/eurheartj/ehz962
  8. Gui Y, Zheng H, Cao RY. Foam Cells in Atherosclerosis: Novel Insights Into Its Origins, Consequences, and Molecular Mechanisms. Front Cardiovasc Med. 2022;9:845942. doi: 10.3389/fcvm.2022.845942
  9. Pryma CS, Ortega C, Dubland JA, Francis GA. Pathways of smooth muscle foam cell formation in atherosclerosis. Curr Opin Lipidol. 2019;30(2):117-124. doi: 10.1097/MOL.0000000000000574
  10. Barrett TJ. Macrophages in Atherosclerosis Regression. Arterioscler Thromb Vasc Biol. 2020;40(1):20-33. doi: 10.1161/ATVBAHA.119.312802
  11. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045-2051. doi: 10.1161/ATVBAHA.108.179705
  12. Sheedy FJ, Grebe A, Rayner KJ, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14(8):812-820. doi: 10.1038/ni.2639
  13. Warner SJ, Auger KR, Libby P. Interleukin 1 induces interleukin 1. II. Recombinant human interleukin 1 induces interleukin 1 production by adult human vascular endothelial cells. J Immunol. 1987;139(6):1911-1917. PMID: 3497983
  14. Libby P. Interleukin-1 Beta as a Target for Atherosclerosis Therapy: Biological Basis of CANTOS and Beyond. J Am Coll Cardiol. 2017;70(18):2278-2289. doi: 10.1016/j.jacc.2017.09.028
  15. McHale JF, Harari OA, Marshall D, Haskard DO. TNF-alpha and IL-1 sequentially induce endothelial ICAM-1 and VCAM-1 expression in MRL/lpr lupus-prone mice. J Immunol. 1999;163(7):3993-4000. PMID: 10491002.
  16. Hou Z, Falcone DJ, Subbaramaiah K, Dannenberg AJ. Macrophages induce COX-2 expression in breast cancer cells: role of IL-1β autoamplification. Carcinogenesis. 2011;32(5):695-702. doi: 10.1093/carcin/bgr027
  17. Loppnow H, Libby P. Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest. 1990;85(3):731-738. doi: 10.1172/JCI114498
  18. Libby P, Warner SJ, Friedman GB. Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest. 1988;81(2):487-498. doi: 10.1172/JCI113346
  19. Ma XF, Zhou YR, Zhou ZX, et al. TRIM65 Suppresses oxLDL-induced Endothelial Inflammation by Interaction with VCAM-1 in Atherogenesis. Curr Med Chem. 2024;31(30):4898-4911. doi: 10.2174/0929867331666230822152350
  20. Wung BS, Ni CW, Wang DL. ICAM-1 induction by TNFalpha and IL-6 is mediated by distinct pathways via Rac in endothelial cells. J Biomed Sci. 2005;12(1):91-101. doi: 10.1007/s11373-004-8170-z
  21. Wesemann DR, Benveniste EN. STAT-1 alpha and IFN-gamma as modulators of TNF-alpha signaling in macrophages: regulation and functional implications of the TNF receptor 1:STAT-1 alpha complex. J Immunol. 2003; 171(10):5313-5319. doi: 10.4049/jimmunol.171.10.5313
  22. Snegova VA, Pigarevsky PV, Maltseva SV, Yakovleva OG. The involvement of interferon-gamma and tumor necrosis factor-alpha in the formation of unstable atherosclerotic plaque. Medical Academic Journal. 2024;24(1):59-66. doi: 10.17816/MAJ629096
  23. Vendrov AE, Sumida A, Canugovi C, et al. NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis. Redox Biol. 2019;21:101063. doi: 10.1016/j.redox.2018.11.021
  24. Zhang R, Xu Y, Ekman N, et al. Etk/Bmx transactivates vascular endothelial growth factor 2 and recruits phosphatidylinositol 3-kinase to mediate the tumor necrosis factor-induced angiogenic pathway. J Biol Chem. 2003;278(51):51267-76. doi: 10.1074/jbc.M310678200
  25. Klouche M, Bhakdi S, Hemmes M, Rose-John S. Novel path to activation of vascular smooth muscle cells: up-regulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor. J Immunol. 1999;163(8):4583-9. PMID: 10510402
  26. Kayakabe K, Kuroiwa T, Sakurai N, et al. Interleukin-6 promotes destabilized angiogenesis by modulating angiopoietin expression in rheumatoid arthritis. Rheumatology (Oxford). 2012;51(9):1571-1579. doi: 10.1093/rheumatology/kes093
  27. Zhang Y, Yang X, Bian F, et al. TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: crosstalk between NF-κB and PPAR-γ. J Mol Cell Cardiol. 2014;72:85-94. doi: 10.1016/j.yjmcc.2014.02.012
  28. Nazarov PG, Maltseva ON, Tanyanskiy DA, et al. The effect of inflammatory factors on transendothelial transport of serum lipoproteins in vitro. Cytokines and inflammation. 2015;14(4):59-64. EDN: WXDWEZ
  29. Jia X, Liu Z, Wang Y, et al. Serum amyloid A and interleukin -1β facilitate LDL transcytosis across endothelial cells and atherosclerosis via NF-κB/caveolin-1/cavin-1 pathway. Atherosclerosis. 2023;375:87-97. doi: 10.1016/j.atherosclerosis.2023.03.004
  30. Pigarevsky PV, Snegova VA, Maltseva SV, Davydova NG. T-lymphocytes and macrophages in unstable atherosclerotic lesions in humans. Cytokines and inflammation. 2015;14(2):84-87. EDN: UZQGZH
  31. Ivanova AA, Dmitrieva AA, Denisenko AD. Antibodies to low-density lipoproteins modified with malone dialdehyde: blood content and role in atherogenesis. Medical immunology. 2025;27(1):131-142. doi: 10.15789/1563-0625-ATL-2955
  32. Porsch F, Binder CJ. Autoimmune diseases and atherosclerotic cardiovascular disease. Nat Rev Cardiol. 2024;21(11):780-807. doi: 10.1038/s41569-024-01045-7
  33. Wuttge DM, Zhou X, Sheikine Y, et al. CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2004;24(4):750-755. doi: 10.1161/01.ATV.0000124102.11472.36
  34. Denisenko AD, Bovtyushko PV, Yusupov AN. Pathogenesis of atherosclerosis. In book Pathophysiology of metabolism; ed. by V.N. Tsygan. St. Petersburg: SpetsLit Publ., 2013, pp. 143-164.
  35. Niemann-Jönsson A, Ares MP, Yan ZQ, et al. Increased rate of apoptosis in intimal arterial smooth muscle cells through endogenous activation of TNF receptors. Arterioscler Thromb Vasc Biol. 2001;21(12):1909-1914. doi: 10.1161/hq1201.100222
  36. Saren P, Welgus HG, Kovanen PT. TNF-alpha and IL-1beta selectively induce expression of 92-kda gelatinase by human macrophages. J Immunol. 1996;157:4159–4165. PMID: 8892653
  37. Pigarevsky PV, Maltseva SV, Tatarinov AE, et al. Matrix metalloproteinase type 1 in the blood of patients with coronary artery disease and atherosclerotic lesions in humans. Cytokines and inflammation. 2016;15(1):61-65. EDN: XAHNOH
  38. Hansson GK, Hellstrand M, Rymo L, et al. Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells. J Exp Med. 1989;170(5):1595-1608. doi: 10.1084/jem.170.5.1595
  39. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb. 1991;11(5):1223-1230. doi: 10.1161/01.atv.11.5.1223.
  40. Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J Intern Med. 2015;278(5):483-93. doi: 10.1111/joim.12406
  41. Larionova EE, Denisenko AD. High-Density Lipoproteins Protect Macrophage-Like Cells from Apoptosis Caused by Oxidized Low-Density Lipoproteins and TNF-α. Cell Tiss. Biol. 2024;18,671–679.doi: 10.1134/S1990519X24700573
  42. Kasikara C, Doran AC, Cai B, Tabas I. The role of non-resolving inflammation in atherosclerosis. J Clin Invest. 2018;128(7):2713-2723. doi: 10.1172/JCI97950
  43. Bäck M, Yurdagul A Jr, Tabas I, et al. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019;16(7):389-406. doi: 10.1038/s41569-019-0169-2
  44. Thondapu V, Kurihara O, Yonetsu T, et al. Comparison of Rosuvastatin Versus Atorvastatin for Coronary Plaque Stabilization. Am J Cardiol. 2019;123(10):1565-1571. doi: 10.1016/j.amjcard.2019.02.019
  45. Mallat Z, Gojova A, Marchiol-Fournigault C, et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001;89(10):930-4. doi: 10.1161/hh2201.099415
  46. Sharma M, Schlegel MP, Afonso MS, et al. Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression. Circ Res. 2020;127(3):335-353. doi: 10.1161/CIRCRESAHA.119.316461
  47. Chinetti-Gbaguidi G, Baron M, Bouhlel MA, et al. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ Res. 2011;108(8):985-995. doi: 10.1161/CIRCRESAHA.110.233775
  48. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451-83. doi: 10.1146/annurev.immunol.021908.132532
  49. Proto JD, Doran AC, Gusarova G, et al. Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution. Immunity. 2018;49(4):666-677. doi: 10.1016/j.immuni.2018.07.015
  50. Pigarevskiy PV, Maltseva SV, Snegova VA. Progressive atherosclerotic lesions in humans. Morphological and immuno-inflammatory aspects. Cytokines and inflammation. 2013;12(1-2):5-12. EDN: RVTFLB
  51. Conrad N, Verbeke G, Molenberghs G, et al. Autoimmune diseases and cardiovascular risk: a population-based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UK. Lancet. 2022;400(10354):733-743. doi: 10.1016/S0140-6736(22)01349-6
  52. Kurt B, Reugels M, Schneider KM, et al. C-reactive protein and cardiovascular risk in the general population. Eur Heart J. 2025:ehaf937. doi: 10.1093/eurheartj/ehaf937
  53. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20-28. doi: 10.1056/NEJMoa042378
  54. Ridker PM. How Common Is Residual Inflammatory Risk? Circ Res. 2017;120(4):617-619. doi: 10.1161/CIRCRESAHA.116.310527
  55. Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024;45(36):3415-3537. doi: 10.1093/eurheartj/ehae177
  56. Ridker PM, Devalaraja M, Baeres FMM, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021;397(10289):2060-2069. doi: 10.1016/S0140-6736(21)00520-1
  57. Ridker PM, Baeres FMM, Hveplund A, et al. Rationale, Design, and Baseline Clinical Characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 Inhibition and Atherosclerotic Event Rate Reduction. JAMA Cardiol. 2025 Dec 10. doi: 10.1001/jamacardio.2025.4491. Online ahead of print.
  58. d'Entremont MA, Poorthuis MHF, Fiolet ATL, et al. Colchicine for secondary prevention of vascular events: a meta-analysis of trials. Eur Heart J. 2025;46(26):2564-2575. doi: 10.1093/eurheartj/ehaf210
  59. Nidorf SM, Ben-Chetrit E, Ridker PM. Low-dose colchicine for atherosclerosis: long-term safety. Eur Heart J. 2024;45(18):1596-1601. doi: 10.1093/eurheartj/ehae208
  60. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-2505. doi: 10.1056/NEJMoa1912388
  61. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-1847. doi: 10.1056/NEJMoa2021372
  62. Jacobsson LT, Turesson C, Gülfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005;32(7):1213-1218. PMID: 15996054.
  63. Mo B, Ding Y, Ji Q. NLRP3 inflammasome in cardiovascular diseases: an update. Front Immunol. 2025;16:1550226. doi: 10.3389/fimmu.2025.1550226
  64. Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2025;85(22):2135-2237. doi: 10.1016/j.jacc.2024.11.009
  65. Sager HB, Heidt T, Hulsmans M, et al. Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction. Circulation. 2015;132(20):1880-1890. doi: 10.1161/CIRCULATIONAHA.115.016160
  66. Antoniades C, Tousoulis D, Vavlukis M, et al. Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers. Eur Heart J. 2023;44(38):3827-3844. doi: 10.1093/eurheartj/ehad484
  67. Kamaly N, Fredman G, Fojas JJ, et al. Targeted Interleukin-10 Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis. ACS Nano. 2016;10(5):5280-5292. doi: 10.1021/acsnano.6b01114
  68. Fredman G, Kamaly N, Spolitu S,et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med. 2015;7(275):275ra20. doi: 10.1126/scitranslmed.aaa1065
  69. Fredman G, Hellmann J, Proto JD, et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun. 2016;7:12859. doi: 10.1038/ncomms12859
  70. Huang X, Liu C, Kong N, et al. Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages. Nat Protoc. 2022;17(3):748-780. doi: 10.1038/s41596-021-00665-4
  71. Sriranjan R, Zhao TX, Tarkin J, et al. Low-dose interleukin 2 for the reduction of vascular inflammation in acute coronary syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial. BMJ Open. 2022;12(10):e062602. doi: 10.1136/bmjopen-2022-062602
  72. Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A. 1995;92(3):821-825. doi: 10.1073/pnas.92.3.821
  73. Ketlinsky SA, Denisenko AD, Pigarevsky PV, et al. The effect of immunization of C57BL/6J mice with peroxide-modified low-density lipoproteins on the severity of atherosclerotic lesions. Arkhiv Patologii. 2011;73(4):38-41. EDN: OFYLEL
  74. Nilsson J, Wigren M, Shah PK. Vaccines against atherosclerosis. Expert Rev Vaccines. 2013;12(3):311-321. doi: 10.1586/erv.13.4
  75. Farina CJ, Lu W, Nilsson J. Orticumab: the potential to harness oxidized LDL to reduce coronary inflammation with plaque-targeted therapy. Curr Opin Lipidol. 2025;36(4):170-178. doi: 10.1097/MOL.0000000000000990

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