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Abstract

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.

Keywords

atherosclerosis JAK/STAT cytokines inflammation apoptosis

Background

Atherosclerosis is a serious disease that is responsible for causing coronary heart disease, cerebral infarction, and peripheral vascular disease. It is characterized by the accumulation of lipids in certain arteries, leading to the growth of plaques on the arterial walls. This process is accompanied by the proliferation of smooth muscle cells and fiber components, which can result in tissue necrosis and disintegration within the plaques. The combination of these factors leads to the formation of atherosclerotic substances, ultimately resulting in atherosclerosis. Atherosclerotic diseases claim the lives of approximately 20 million people worldwide each year.¹ Despite advancements in modern medical treatments such as drug therapy, surgery, and interventional therapy, the incidence of atherosclerosis continues to rise.

Over the past two decades, there has been increasing recognition of the relationship between cardiovascular disease, atherosclerosis, and inflammation as research in this area has progressed.² Atherosclerosis is widely acknowledged as a chronic inflammatory disease, with the inflammatory response playing a crucial role in every stage of its development.³ The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway has recently emerged as a target for inflammation research. It plays a key role in the development of autoimmune diseases and has shown promise as a therapeutic target for inflammatory conditions such as inflammatory bowel disease.⁴ This pathway also affects vascular diseases such as atherosclerosis and arterial hypertension through angiotensin II effects, mechanical stress, oxidative stress, and Interleukin-6/Glycoprotein130 activation.⁵ Researchers have discovered that, apart from inflammation, other pathogenic mechanisms such as apoptosis and pyroptosis also significantly contribute to the development of atherosclerosis. The JAK/STAT signaling pathway plays a crucial role in mediating the impact of these mechanisms on atherosclerosis.

In this article, we will outline various mechanisms through which the JAK/STAT signaling pathway influences atherosclerosis. Additionally, we will provide a detailed analysis of the downstream cytokines associated with representative JAK/STAT signaling pathways and their current applications in the treatment of atherosclerosis and its hardening. It provides new ideas for treating atherosclerosis.

Path Introduction

The Janus kinase/signal transducer and activator of transcription (JAK/STAT pathway) signaling pathway is mainly composed of three parts: tyrosine kinase-associated receptors that receive signals, tyrosine kinase JAK that transmits signals, and signal transduction STAT.⁶ The JAK/STAT signaling pathway operates in a series of steps. Cytokines interact with JAK receptors, leading to the phosphorylation of specific tyrosine residues in the receptors. This phosphorylation enables the binding and phosphorylation of STATs with SH2 domains. The activated and phosphorylated STATs then form dimers through intermolecular interactions. These dimers are then transferred to the nucleus where they regulate the expression of genes related to cytokine signaling.⁷ The process can be seen in Figure 1.

Figure 1.

Mechanism diagram of JAK/STAT signaling pathway. JAK, Janus kinase; STAT, signal transducer and activator of transcription; P, phosphorylation.

The JAK family is composed of nonreceptor tyrosine kinases renamed “Janus kinases.”⁸ It can phosphorylate both the cytokine receptors bound to it and multiple specific signaling molecules of the SH2 domain. The JAK family comprises four members, namely JAK1, JAK2, JAK3, and TYK2.

Signal transducer and activator of transcription (STAT) is a crucial transcription factor in the immune response process. It acts as the downstream target of JAKs and is involved in various aspects, including cellular immunity, apoptosis, and differentiation. The STAT family comprises seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6.⁹ STAT contains SH2 and SH3 domains, which can form various heterologous or homologous dimers and bind to specific peptide segments containing phosphorylated tyrosine.^7,10

JAK/STAT Affects Atherosclerosis by Regulating Inflammatory Factors

The JAK/STAT signaling pathway is crucial for coordinating immune and inflammatory responses. Atherosclerosis is now generally considered a chronic inflammatory disease,³ and there are many theories and experiments that have proven that atherosclerosis can be improved by regulating the JAK/STAT signaling pathway.^11,12 In this study, we present a list of several well-established inflammatory factors that have been identified as downstream factors of JAK/STAT and are known to directly affect the development of atherosclerosis. Based on these findings, we hypothesize that the regulation of the JAK/STAT signaling pathway can be influenced by these inflammatory factors, thereby impacting atherosclerosis.

Suppressor of Cytokine Signaling (SOCS)

The full name of SOCS is suppressor of cytokine signaling. The combination of cytokines and their corresponding receptors can activate signal transduction pathways, transmitting the cytokine signal from the cell membrane to the cytoplasm, and ultimately to the nucleus, resulting in the expression of the target gene. SOCS serves as a negative feedback regulator of the classic JAK/STAT signaling pathway and is also a downstream target gene of this pathway. SOCS can bind to phosphotyrosine on the receptor, preventing the recruitment of STAT to the receptor. It can also directly bind to the JAK receptor, inhibiting JAK activity. Additionally, activated STATs can stimulate the transcription of SOCS genes.¹³

The SOCS family comprises eight proteins, namely SOCS1 to 7 and CIS.¹⁴ Among them, SOCS1 and SOCS3 are closely associated with atherosclerosis. These two molecules exhibit antiinflammatory and protective effects on atherosclerosis in various vascular cells including monocytes, endothelial cells, and vascular smooth muscle cells.¹⁵ However, it is important to note that these two molecules play distinct roles in the progression of atherosclerosis.

Experimental studies have demonstrated that in ApoE mice fed with a high-fat diet, the expression of SOCS1 in the aortic root plaque initially increased and subsequently decreased as the feeding time was prolonged. Conversely, the expression of SOCS3 increased over time. Additionally, it was observed that in the non-CHD population, there was a positive correlation between serum total cholesterol level and SOCS3 expression.¹⁶ In a separate study, the researchers observed that when the SOCS1 gene was eliminated in mice prone to atherosclerosis, there was a significant increase in the expression of proinflammatory cytokines in SOCS1-knockout mice. Additionally, there was an increase in lipid deposition and macrophage expression after the knockout of the SOCS1 gene. The results also showed changes in the components of atherosclerotic plaques due to the loss of SOCS1. These experimental findings suggest that SOCS1 plays a protective role against atherosclerosis in mice used as a model for studying this condition.¹⁷ Furthermore, in diabetic atherosclerotic mice, the researchers observed that the enhanced expression of SOCS1 effectively improved atherosclerosis and inflammation.¹⁸

Contrary to the impact of SOCS1, the absence of SOCS3 in T cells has been observed to hinder the progression of atherosclerosis.¹⁹ In a recent study focusing on platelets and atherosclerosis, it was discovered that platelets stimulate the expression of SOCS3, leading to a decrease in the ratio between SOCS1 and SOCS3. Consequently, this accelerates the onset of inflammation and atherosclerosis. Additionally, the study demonstrated that the upregulation of SOCS3 expression contributes to the advancement of atherosclerosis.²⁰

The current research primarily focuses on investigating the negative feedback regulation of SOCS on the JAK/STAT signaling pathway. However, there is limited theoretical evidence to support the direct impact of the JAK/STAT signaling pathway on the progression of atherosclerosis through the regulation of SOCS gene expression. It is possible that the negative feedback effect of SOCS on the JAK/STAT signaling pathway outweighs the stimulating effect of STAT on SOCS protein transcription, leading to the formation and development of atherosclerosis. Nevertheless, further experimental research is required to validate this hypothesis based on previous research findings.

Interleukin 6 (IL-6)

Interleukins are lymphokines that facilitate communication between white blood cells or immune cells, and they play a crucial role in various processes such as the maturation, activation, proliferation, differentiation, and regulation of immune cells. Moreover, they also contribute to numerous physiological processes and pathological reactions in the body. Currently, 38 interleukins have been identified and numbered based on the order of their discovery. These interleukins are classified into different groups based on their distinct structural features.²¹ The current classification includes six families: IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family, and IL-17 family.²² Among these families, IL-6 in the IL-6 family is closely associated with inflammation and the progression of atherosclerosis.

IL-6, a soluble mediator, has various effects on inflammation, immune response, and hematopoiesis. Human IL-6 is composed of 212 amino acids, including a 28 amino acid signal peptide.²³ IL-6 exhibits both proatherogenic and antiatherogenic effects. The proatherogenic effect is attributed to IL-6's ability to attract neutrophils, monocytes, and macrophages.²⁴ Increased expression of IL-6 promotes atherosclerosis,²⁵ and genetic studies have confirmed a causal relationship between IL-6 signaling and atherosclerosis.²⁶ In a survey conducted by Joseph et al, it was observed that the severity of carotid artery plaques was positively associated with the expression of IL-6. The study involved 5888 participants, and it was found that higher levels of IL-6 in plasma were linked to more severe cervical atherosclerosis.²⁷ However, recent studies on atherosclerotic model mice have revealed that the expression of IL-6 can significantly impact the stability of atherosclerotic plaques in mice.²⁸ Additionally, when IL-6 was knocked out in ApoE-deficient mice, it was discovered that the deletion of the IL-6 gene might increase the likelihood of atherosclerotic plaque formation.²⁹

The JAK/STAT signaling pathway plays a role in promoting inflammation and atherosclerosis by increasing the expression of IL-6.³⁰ Targeting downstream kinases or transcription factors in this pathway has emerged as a potential approach for treating atherosclerosis.³¹ JAK inhibitors, such as tofacitinib and baricitinib, have been shown to effectively inhibit the JAK/STAT signaling pathway and its downstream factors, including IL-6.³² Studies conducted on ApoE-deficient mice have demonstrated that the use of tofacitinib in a specific dosage not only reduces the expression of IL-6, but also improves atherosclerosis and reduces the formation of foam cells.³³ However, it is still uncertain whether JAK inhibitors have an impact on human atherosclerosis, and further research is required. While this article focuses on IL-6 as a representative factor, other members of the IL family may also be associated with Atherosclerosis to some extent. If possible in the future, we will investigate the relationship between other IL family factors and Atherosclerosis.

Interferon-Gamma (IFN-γ)

Interferons, a class of glycoproteins, exhibit antiviral, cell proliferation-inhibiting, immune-modulating, and antitumor effects.³⁴ Among them, IFN-γ is classified as a type II interferon. Human IFN-γ is produced by T cells and NK cells. It plays a crucial role in various immune response processes related to atherosclerosis and is capable of activating macrophages. Additionally, it stimulates the production of proinflammatory cytokines and enhances the expression of adhesion molecules, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).^24,35

According to current research, the majority of views suggest that IFN-γ is a proatherosclerotic factor.^24,35 In a study conducted by Stewart C. Whitman et al, it was found that ApoE mice injected with recombinant IFN-γ had a significantly larger area of ascending aortic atherosclerotic lesions compared to ApoE mice injected with phosphate-buffered saline.³⁶ While some studies have indicated that IFN-γ may have a short-term preventive and therapeutic effect on arterial stenosis by inhibiting the expression of vascular smooth muscle cells (VSMCs),³⁷ this perspective is not widely accepted.

In the JAK/STAT signaling pathway, STAT1 and STAT2 activate the expression of interferon-stimulated genes (ISGs). STAT1 homodimers, also known as gamma-activating factor (GAF), directly bind to genes containing IFN-II activation sites to activate the transcription of all types of IFN.³⁸ Additionally, the interaction of IFN receptors on the cell surface leads to the activation of JAK kinases, which phosphorylate STATs to positively regulate the JAK/STAT signaling pathway.³⁹ Consequently, IFN-γ also acts as a common inducer of the JAK/STAT signaling pathway.

Given that interferon relies on the JAK/STAT signaling pathway for transduction, it is possible to achieve therapeutic effects on interferon-mediated diseases by blocking the JAK pathway.⁴⁰ In humans, the JAK inhibitor tofacitinib has been shown to inhibit IFN-γ signaling.⁴¹ Similarly, in a study involving systemic lupus erythematosus model mice, the JAK2 2inhibitor CEP-33779 demonstrated the ability to reduce various inflammatory cytokines, including IFN-γ production.⁴² However, further in-depth research is necessary to determine the impact of JAK inhibitors on human atherosclerosis.

Tumor Necrosis Factor Alpha (TNF-α)

TNF-α is an inflammatory cytokine that is produced by macrophages and monocytes during acute inflammation.⁴³ It is also considered one of the proatherogenic cytokines.²⁴ TNF-α can cause damage to vascular endothelial cells in various ways. For example, it up-regulates the expression of VCAM-1 in vascular endothelial cells. VCAM-1 facilitates the adherence of monocytes to endothelial cells and their movement from the vascular intima to the middle layer of blood vessels. This process further leads to the release of TNF-α and other inflammatory cytokines, creating a vicious circle that accelerates plaque formation and worsens the severity of atherosclerosis.⁴⁴

In patients with atherosclerosis, the expression level of TNF-α is significantly higher compared to normal individuals, and this is correlated with the severity of atherosclerosis.⁴⁵ Knockdown of TNF-α was found to reduce the expression of adhesion molecules in human umbilical vein endothelial cells (HUVECs).⁴⁶ Additionally, it was discovered that Brucea Brucella, a substance that inhibits the expression of recombinant tumor necrosis factor receptor 1 (TNFR1), can further suppress TNF-α and significantly inhibit the progression of atherosclerosis in mice.⁴⁷ Simvastatin, a member of the statin family, can effectively treat atherosclerosis by reducing the expression of TNF-α-induced VCAM-1.⁴⁸

TNF-α is influenced by the JAK/STAT signaling pathway. Multiple studies have demonstrated that inhibiting this pathway can impact the expression of TNF-α.^49–51 Furthermore, when investigating the effect of inhibiting the JAK/STAT signaling pathway on atherosclerosis, it has been observed that the expression level of TNF-α is reduced.¹¹ These findings indicate that the significance of TNF-α should not be overlooked when it comes to its role in atherosclerosis through the inhibition of the JAK/STAT signaling pathway.

Transforming Growth Factor-β (TGF-β)

TGF-β is a group of cytokines recently discovered to regulate cell growth and differentiation. It is part of the TGF-β superfamily, which also includes activin (activins), inhibins, Mullerian inhibitor substance (MIS), and bone morphogenetic proteins (BMPs).⁵² TGF-β is produced by various inflammatory cells.²⁴ It affects cardiac function by influencing cell proliferation, differentiation, migration, adhesion, apoptosis, and extracellular matrix production. Furthermore, it has effects on vascular function.⁵³

Based on current research findings, TGF-β plays a dual role in the formation and development of atherosclerosis. On one hand, TGF-β expressed in endothelial cells has been found to accelerate vascular inflammation. In hyperlipidemia model mice, inhibiting TGF-β expression in endothelium has been shown to reduce the severity of vascular wall inflammation.⁵⁴ Several experiments have demonstrated that inhibiting TGF-β expression can improve atherosclerosis.^55,56 On the other hand, under certain circumstances, upregulation of TGF-β to a certain extent can have an antiatherosclerotic effect.^57,58

The relationship between the JAK/STAT signaling pathway and TGF-β is highly significant. Previous studies have confirmed the presence of two potential STAT3 binding sites in the promoter region of the TGF-β gene, indicating that STAT3 can directly regulate TGF-β transcription.⁵⁹ In summary, the available evidence suggests that both upregulation and inhibition of TGF-β expression can contribute to the inhibition of atherosclerosis. However, determining the appropriate timing, method, and level of TGF-β expression to effectively suppress cardiovascular inflammation requires further investigation.

JAK/STAT Affects Atherosclerosis by Regulating Apoptotic Factors

Apoptosis, which is also referred to as programmed cell death, is a form of cell death that is actively controlled by genes in nucleated cells.⁶⁰ Studies have shown that apoptosis plays a significant role in the formation and progression of atherosclerosis in both endothelial cells and vascular smooth muscle cells within atherosclerotic plaques.⁶¹ The role of apoptosis in atherosclerosis varies depending on the stage of the plaque and the types of cells involved. During the early stages, apoptosis of macrophages and smooth muscle cells can actually slow down the development of atherosclerotic plaque. However, in later stages, apoptosis may destabilize the plaque and increase the risk of thrombosis.⁶² There is a close relationship between apoptosis and atherosclerosis, with the JAK/STAT signaling pathway playing a role in mediating certain molecules associated with apoptosis and their impact on atherosclerosis.

B-Cell Lymphoma-2 (Bcl-2)

The Bcl-2 family of proteins is widely recognized as the primary regulator of apoptosis. These proteins exert their influence by controlling the permeability of the outer mitochondrial membrane, either promoting or inhibiting apoptosis.⁶³ The Bcl-2 family members can be classified into three categories. The first category comprises the antiapoptotic proteins, such as Bcl-2, Bcl-XL, and Bcl-W, which play a crucial role in inhibiting apoptosis. These proteins possess four BH domains (BH1-4). The second category consists of proapoptotic proteins, including BCL2-associated X (Bax) and BCL2-associated K (Bak), which play a role in promoting apoptosis. These proteins have three BH domains (BH1-3). On the other hand, the third category comprises BH3-only proteins, such as BAD and BID, which solely possess BH3 domains. These proteins can bind and regulate antiapoptotic Bcl-2 proteins to promote apoptosis. Therefore, they are sometimes considered as members of the proapoptotic family.⁶⁴

Bcl-2, the first member of the Bcl-2 family, was initially discovered during the study of the t(14;18) translocation in human follicular lymphomas.⁶⁵ It was identified as an oncogene that promotes tumor growth by inhibiting cell death.⁶⁶ Subsequently, it was confirmed that Bcl-2 has an antiapoptotic effect and can inhibit apoptosis induced by various cytotoxins.⁶⁷ Bcl-XL, which shares similarities with Bcl-2, also possesses the ability to inhibit apoptosis.⁶⁸ In a study by Hui Cao et al, the effect of quercetin on macrophages in early atherosclerosis models was investigated in vitro. The findings showed that quercetin reduced the expression of Bcl-2, thereby promoting the apoptosis and autophagy of macrophages and improving atherosclerosis.⁶⁹ In another experiment investigating the impact of lncRNA on atherosclerosis, it was observed that lncRNA-NORAD (noncoding RNA-activated by DNA damage) can enhance the expression of Bcl-2, leading to a reduction in endothelial apoptosis and an improvement in atherosclerosis.⁷⁰ Jin Zhao et al discovered that upregulation of microRNA-1907 gene expression can hinder the expression of Bcl-2, thus exacerbating atherosclerosis.⁷¹ Multiple experimental findings demonstrate that Bcl-2-mediated apoptosis has dual effects on atherosclerosis.

Bax, a member of the Bcl-2 family, plays a crucial role in promoting apoptosis. Its overexpression can counteract the antiapoptotic effect of Bcl-2, ultimately resulting in cell death.⁷² Research studies have highlighted that the regulation of cell apoptosis is not solely governed by a single gene; rather, the balance between Bax and Bcl-2 levels is pivotal in determining the intensity of apoptosis.⁷³

Bcl-2 and Bax are downstream transcription molecules of STAT.⁷⁴ The expression of STAT can influence the ratio between Bcl-2 and Bax, thereby determining the level of apoptosis. Based on existing experimental results, inhibiting the expression of STAT through various methods leads to a decrease in the expression of antiapoptotic genes like Bcl-2, while promoting the expression of proapoptotic genes like Bax. Conversely, promoting the expression of STAT can increase the expression of Bcl-2 and decrease the expression of Bax.^75–78 So inhibiting the STAT pathway ultimately leads to cell apoptosis. Based on our previous findings, inhibiting the JAK/STAT signaling pathway can enhance the development of Atherosclerosis during the early stages of plaque formation. However, if the goal is to improve atherosclerosis by inhibiting endothelial cell apoptosis after plaque formation, overexpressing STAT may be necessary. It is important to note that this approach may also promote the expression of various inflammatory factors such as IL-6 and TNF-α, which are contrary to the desired improvement in atherosclerosis. Therefore, further experimental and clinical studies are required to determine the specific circumstances.

JAK/STAT Affects Atherosclerosis by Regulating Pyroptosis Factors

Pyroptosis is a form of inflammatory cell death that involves the formation of pores on the cell membrane, resulting in the rupture of the membrane and the release of cell contents and proinflammatory mediators into the interstitium. This process triggers the body's immune response, leading to the recruitment of more inflammatory cells and further amplification of the inflammatory response, ultimately resulting in cell death.⁷⁹ According to research, pyroptosis promotes atherosclerosis through three main pathways: endothelial cell pyroptosis, macrophage pyroptosis, and smooth muscle cell pyroptosis.⁸⁰ The JAK/STAT signaling pathway plays a role in regulating pyroptosis-related factors that impact the development of atherosclerosis.

Gasdermin

The activation of gasdermin (GSDM) family proteins is a significant biochemical characteristic of pyroptosis. Among these proteins, gasdermin D (GSDMD) and gasdermin E (GSDME) play key roles in pyroptosis. GSDMD has been confirmed to regulate the occurrence of pyroptosis by regulating the inflammasome.⁸¹ On the other hand, GSDME can be activated by caspase-3, leading to a transition in cell death from apoptosis to pyroptosis.⁸²

In an in vitro study conducted by Feng Yao, it was observed that knocking out the GSDME gene in HUVECs led to a significant reduction in pyroptosis and inflammatory responses.⁸³ Yuanyuan Wei et al conducted a study on ApoE knockout atherosclerosis model mice and found that the expression of GSDME was upregulated. They further investigated GSDME by using GSDME and ApoE double knockout atherosclerosis model mice as well as ApoE knockout atherosclerosis mice. The results showed that the lesion area and inflammatory response of atherosclerosis in GSDME-knockout mice were smaller compared to the control group. Additionally, they identified the binding site of GSDME promoter on STAT3 and validated GSDME as a transcriptional target of STAT3.⁸⁴

Activation of STAT3 leads to the transcription of GSDME, which in turn increases the expression of caspase-3. This promotes pyroptosis in vascular endothelial cells, vascular smooth muscle cells, and macrophages, ultimately resulting in inflammation and the progression of atherosclerotic lesions. These findings indicate that suppressing JAK/STAT signaling can also inhibit GSDME expression, leading to improved inflammation control and atherosclerosis development.

NLR Family, Pyrin Domain Containing 3 (NLRP3)

NLRP3 is an inflammasome, a complex composed of various proteins. Once activated, NLRP3 triggers the self-cleavage and activation of inactive procaspase-1, resulting in the generation of active caspase-1. This leads to caspase-1-dependent cell death and further promotes inflammation by secreting sex factors IL-1β and IL-18, ultimately exacerbating inflammation.⁸⁵

Reducing the expression of NLRP3 can decrease the lipid content of the plaque and enhance the collagen content of the plaque. This, in turn, increases the stability of the plaque. Additionally, it can suppress the expression of proinflammatory factors, thereby reducing the pyroptosis of macrophages and endothelial cells and slowing down the progression of atherosclerotic disease.⁸⁶ In their study on the neuroprotective effect of JAK2 inhibition on ischemic stroke, Zhu et al discovered that lentiviral transfection to inhibit the expression of STAT3 also resulted in the inhibition of NLRP3 expression. This finding suggests a direct regulation of NLRP3 inflammatory bodies by STAT3 signaling.⁸⁷ These findings offer new insights into the potential improvement of atherosclerosis by targeting the JAK/STAT signaling pathway and subsequently inhibiting NLRP3 expression.

JAK/STAT Affects Atherosclerosis by Regulating Autophagy Factors

Autophagy is a molecular mechanism that involves the degradation of pathogens and damaged intracellular organelles like mitochondria through lysosomes. It can also eliminate other cellular components, including inflammatory factors and cytokines.⁸⁸ Recent studies have shown that the activation or inhibition of autophagy can have an impact on the development of atherosclerotic plaque.⁸⁹ Similar to pyroptosis, autophagy also plays a role in the development of atherosclerosis by impacting endothelial cells, vascular smooth muscle cells, and macrophages.^90,91 The JAK/STAT signaling pathway has been found to regulate autophagy, which in turn affects atherosclerosis either directly or indirectly.

As a member of the STATs family, STAT3 has a direct regulatory effect on autophagy, which is bidirectional. Firstly, STAT3 promotes the expression of antiautophagy-related proteins BCL-2 and myeloid cell leukemia-1 (MCL-1), inhibiting autophagy. Additionally, STAT3 in the cytoplasm inhibits autophagy through interaction with eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) and Forkhead Box O (FOXO). Secondly, STAT3 in the nucleus enhances the expression of autophagy genes such as hypoxia-inducible factor 1-alpha (HIF-1α), Unc-51 like autophagy activating kinase 2 (ULK2), Bcl2/adenovirus E1B interacting protein 3 (BNIP3), and recombinant beclin 1 (BECN1), indirectly promoting autophagy.⁹²

To date, there has been limited exploration into the potential use of the JAK/STAT signaling pathway to regulate autophagy in the context of atherosclerosis. However, our discussion has revealed a strong connection between JAK/STAT, autophagy, and atherosclerosis. Therefore, it is crucial to conduct further discussions and experiments to fully understand the impact of utilizing the JAK/STAT signaling pathway in the development of atherosclerosis.

Discussion

Atherosclerosis is a complex condition with multiple contributing factors that have not yet been fully understood. Hypertension, hyperlipidemia, diabetes, and obesity are the primary risk factors for the development of atherosclerosis. Some potential factors have been discovered, such as genetic factors, environmental factors, and intestinal microbiota factors.¹ The clinical manifestations of atherosclerosis can be quite alarming. Individuals with coronary atherosclerosis may experience angina pectoris, arrhythmia, or even sudden death if the stenosis of the coronary artery exceeds 75%. Atherosclerosis can also lead to cerebral ischemia, brain atrophy, frequent nocturia, and impaired renal function in cases of renal atherosclerosis. Severe lower extremity atherosclerosis can even result in gangrene.⁹³ The timely detection and intervention of atherosclerosis are receiving increasing attention in the academic community.

The JAK/STAT signaling pathway was initially identified as an important pathway associated with inflammation. Further research has revealed that this pathway also influences other mechanisms, including oxidative stress, apoptosis, pyroptosis, and autophagy. Additionally, the involvement of the JAK/STAT signaling pathway in atherosclerosis has been gradually uncovered. Numerous experiments and studies have consistently demonstrated the influence of regulating the JAK/STAT signaling pathway on the progression of atherosclerosis. This pathway exerts its impact on atherosclerosis development either directly or indirectly by modulating various cytokines (Table 1). This article chooses these factors to focus on because these factors are relatively common and there are many related documents, which are relatively more convincing.

Table 1.

Interactions of the Different Cytokines With the JAK/STAT Signaling Pathway and Their Role in the Development of Atherosclerosis Including the Different Treatments.

Cytokine	Relationship with JAK/STAT	Relationship with atherosclerosis	Suggested treatment
SOCS	Inhibition of JAK/STAT Promoted by JAK/STAT	SOCS1 inhibits AS SOCS3 promotes AS	Further research is needed
1L-6	Promoted by JAK/STAT	Dual action	Inhibition of IL-6,
IFN-y	Bidirectional promotion	Promote AS	Inhibition of I FN-y
TNF-α	Promoted by JAK/STAT	Promote AS	Inhibition of TNF-α
TGF-β	Bidirectional promotion	Dual action	Further research is needed
Bcl–2/Bax	Promoted by JAK/STAT	Improve early AS	Further research is needed
GSDME	Promoted by JAK/STAT	Promote AS	Inhibition of GSDME
NLRP3	Promoted by JAK/STAT	Promote AS	Inhibition of NLRP3
Autophagy factors	Dual action	Dual action	Further research is needed

Abbreviations: SOCS, suppressor of cytokine signaling; IL-6, interleukin-6, IFN-γ: interferon-gamma; TNF-α, tumor necrosis factor alpha; TGF- β, transforming growth factor-β; Bcl-2, B-cell lymphoma-2; Bax, BCL2-associated X; GSDME, gasdermin E; NLRP3, NLR family, pyrin domain containing 3; AS, atherosclerosis.

Based on our analysis of the downstream cell molecules involved in JAK/STAT signaling pathways, it has been observed that manipulating these pathways can potentially hinder the progression of atherosclerosis. However, this research suggests that inhibiting the expression of JAK/STAT signaling pathways may have a more pronounced effect on treating atherosclerosis.⁸ JAK inhibitors, which selectively target JAK kinases and block the JAK/STAT pathway, are currently being investigated for their potential in treating various blood system diseases, tumors, rheumatoid arthritis, and psoriasis. Currently, JAK inhibitors are mainly used clinically for immune system diseases, and multiple JAK inhibitors have entered clinical research..⁹⁴ Various JAK inhibitors have been approved by the FDA for different medical conditions. These include ruxolitinib for blood diseases, tofacitinib, filgotinib, and peficitinib for rheumatoid arthritis, baricitinib and ritlecitinib for alopecia areata and moderate to severe Crohn's disease, upadacitinib, delgocitinib, and Abrocitinib for atopic dermatitis, golidocitinib for T-cell lymphoma, ruxolitinib, fedratinib, and pacritinib for myelofibrosis, Deucravacitinib for psoriasis. Additionally, there are ongoing clinical trials for other JAK inhibitors like CTP-543, jaktinib, and SHR0302. For instance, tofacitinib has been found to inhibit IL-6 and IFN-γ downstream of the JAK/STAT pathway.^33,40 However, the specific impact of JAK inhibitors on atherosclerosis in clinical settings is yet to be confirmed.

To further develop targeted drugs for the treatment of atherosclerosis and improve patient outcomes, it is crucial to conduct comprehensive research on the significance of the JAK/STAT signaling pathway in this condition. Exploring the potential of JAK inhibitors can offer novel perspectives for future therapeutic approaches in atherosclerosis.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Fengxia Zhang

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The Role of JAK/STAT Signaling Pathway and Its Downstream Influencing Factors in the Treatment of Atherosclerosis

Abstract

Keywords

Background

Path Introduction

JAK/STAT Affects Atherosclerosis by Regulating Inflammatory Factors

Suppressor of Cytokine Signaling (SOCS)

Interleukin 6 (IL-6)

Interferon-Gamma (IFN-γ)

Tumor Necrosis Factor Alpha (TNF-α)

Transforming Growth Factor-β (TGF-β)

JAK/STAT Affects Atherosclerosis by Regulating Apoptotic Factors

B-Cell Lymphoma-2 (Bcl-2)

JAK/STAT Affects Atherosclerosis by Regulating Pyroptosis Factors

Gasdermin

NLR Family, Pyrin Domain Containing 3 (NLRP3)

JAK/STAT Affects Atherosclerosis by Regulating Autophagy Factors

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References