Background: According to the World Health Organisation’s Health Report 2019, approximately 17.18 million people die from cardiovascular disease each year, accounting for more than 30% of all global deaths. Therefore, the occurrence of cardiovascular disease is still a global concern. The transcription factor 21 (TCF21) plays an important role in cardiovascular diseases. This article reviews the regulation mechanism of TCF21 expression and activity and focuses on its important role in atherosclerosis in order to contribute to the development of diagnosis and treatment of cardiovascular diseases. Summary: TCF21 is involved in the phenotypic regulation of vascular smooth muscle cells (VSMCs), promotes the proliferation and migration of VSMCs, and participates in the activation of inflammatory sequences. Increased proliferation and migration of VSMCs can lead to neointimal hyperplasia after vascular injury. Abnormal hyperplasia of neointima and inflammation are one of the main features of atherosclerosis. Therefore, targeting TCF21 may become a potential treatment for relieving atherosclerosis. Key Messages: TCF21 as a member of basic helix-loop-helix transcription factors regulates cell growth and differentiation by modulating gene expression during the development of different organs and plays an important role in cardiovascular development and disease. VSMCs and cells derived from VSMCs constitute the majority of plaques in atherosclerosis. TCF21 plays a key role in regulation of VSMCs’ phenotype, thus accelerating atherogenesis in the early stage. However, TCF21 enhances plaque stability in late-stage atherosclerosis. The dual role of TCF21 should be considered in the translational medicine.

Atherosclerosis (AS) is a common form of cardiovascular disease characterized by lipid accumulation and inflammation in the large arteries and may eventually lead to myocardial infarction and stroke [1]. The main pathological manifestations of AS are subintimal lipid deposition in some parts, accompanied by the proliferation of smooth muscle cells and the increase of fibrous matrix components, which gradually develop into atherosclerotic plaques [2]. The arterial wall at the plaque site is thickened and hardened. After necrosis of the internal tissue of the plaque, it binds to the deposited lipid to form atheromatous substances, and the formation of the plaque can block or reduce local vascular blood flow. AS mainly involves large and medium-sized myoelastic arteries, especially the aorta, coronary artery, and cerebral artery, which often leads to serious consequences such as lumen occlusion or wall rupture and bleeding. Aberrant proliferation of vascular smooth muscle cells (VSMCs) in AS promotes plaque formation, but VSMCs in advanced plaques are beneficial by preventing fibrous cap rupture [3]. Recent studies have found that decreased expression of the transcription factor 21 (TCF21) can inhibit the proliferation and migration of VSMCs and inhibit arterial thrombosis and lumen stenosis [4].

Basic helix-loop-helix (bHLH) transcription factors are key factors in regulating lineage and development-specific gene networks. The bHLH proteins play an important role in a variety of biological processes by controlling the expression of genes related to proliferation [5], apoptosis [6], differentiation [7], autophagy [8], cell cycle [9], cell growth [10], development [11], angiogenesis [12], hematopoiesis [13], and morphogenesis [14]. Therefore, they are closely related to human health. TCF21 is a member of bHLH transcription factors. It regulates cell growth and differentiation by regulating gene expression during the development of different organs and plays an important role in cardiovascular development and disease. In the study of different animal models, it has been found that TCF21 is one of the molecular markers of proepicardial cells [15], and in the study of Xenopus embryos, it was found that in the absence of TCF21, epicardial cells can migrate to the heart and maintain their precursor cell characteristics, but their maturity declined [16]. During mouse heart development, TCF21 is expressed in proepicardial cells that give rise to both cardiac fibroblasts and coronary artery SMCs [17]. Moreover, through genome-wide association GAWs, it has been identified that TCF21 is the pathogenic gene of coronary heart disease-related locus 6q23.2 [18, 19]. In the context of AS, an important biological feature of TCF21 is that it regulates the differentiation of fundamental cells in the developing epicardium. All these indicate that the morphological defects of epicardial integrity may be caused by the absence of TCF21. This is because TCF21 can regulate the differentiation and maturation of proepicardial cells in the early stage of epicardial development. In previous studies, we have learned that TCF21 can promote the development of cardiac fibroblasts and inhibit the differentiation of VSMCs. Most epicardial cells expressing TCF21 are aggregated in the cardiac fibroblast lineage before the beginning of epithelial-mesenchymal transition [20]. In addition, with the development of single-cell sequencing technology, the understanding of the differentiation of epicardial cells is extending. The near-term single-cell analysis of the epicardial model from human pluripotent stem cells showed that different epicardial subgroups were defined by high levels of transcription factor TCF21 or other transcription factors. In the TCF21 population, TCF21high cells can differentiate into cardiac fibroblasts and VSMCs, while TCF21low cells are mainly limited to VSMCs [21]. Taken together, these studies demonstrate the complex regulatory role of TCF21 in fundamental cell fate determination during cardiac development.

In addition, in the process of AS, smooth muscle cells (SMCs) from the vascular wall participate in the fibrous cap and potential necrotic core through a process called “phenotypic regulation.” In this process, VSMCs dedifferentiate, proliferate and migrate under the stimulation of AS [22, 23]. TCF21 promotes the proliferation and migration of VSMCs. The enhancement of proliferation and migration of VSMCs will lead to the proliferation of neointima after vascular injury [24, 25], which will lead to lumen restenosis and aggravate the occurrence and development of AS. Therefore, the function of TCF21 may interfere with the response of SMC to vascular injury in the disease environment [18]. However, it is now widely believed that VSMCs will stabilize atherosclerotic plaques, which reflects the dual role of TCF21 in AS: on the one hand, inhibiting its expression will lead to limited proliferation of VSMCs, preventing the progress of AS, but on the other hand, loss of TCF21 may easily lead to plaque rupture and subsequent occlusive thrombosis as the capability of TCF21 in plaque stability [26]. Therefore, therapeutic inhibition of TCF21 pathway is expected to reduce the risk of cardiovascular disease. This article reviews the biological role of TCF21 in AS.

Structure of TCF21

TCF21 is a gene located on human chromosome 6q23q24, encoding a functional 20 kDa TCF21 protein [27]. It is composed of 179 amino acids. Its structure is highly conserved among species. The bHLH domain of TCF21 mainly mediates its dimerization and direct interaction with DNA [28, 29]. In addition, TCF21 contains an N-terminal interface domain (amino acids 2–100) and a C-terminal domain (amino acids 80–179). The former mainly mediates the interaction of TCF21 with mitogen-activated protein kinase 1 (MEK1) [30], whereas the latter mainly mediates the interaction between TCF21 and HeLa Ebox-binding protein [31].

Function of TCF21

TCF21 is a bHLH transcription factor that regulates cell growth and differentiation. For example, TCF21 can promote the development of cardiac fibroblasts, inhibit the differentiation of VSMCs of epicardial cells [3], and participate in the control of cell fate and differentiation during the development of coronary artery SMC [32]. TCF21 is also closely related to organ formation because it can regulate the development and differentiation of various cell types [33]. In addition, TCF21 is also involved in the expression of target genes for angiogenesis [34], epithelial-mesenchymal transition [35], cell cycle [36], and autophagy [37] and mediates a variety of physiological and pathological processes.

It is worth noting that TCF21 is also involved in regulating the pro-inflammatory environment and the remodeling of the active extracellular matrix (ECM) of the visceral and subcutaneous fat pads [38]. The multiple functions of TCF21 in biological processes indicate that its dysregulation is closely related to many diseases. Therefore, its physiological function and clinical application need to be further studied.

Phenotypic Transformation of SMCs and Proliferation of Neointima

VSMCs are highly specialized and differentiated cells in adult animals, which together with ECM (round elastic fibers, type I collagen, and proteoglycans) constitute the media layer of blood vessels [39]. The main function of VSMCs is to regulate the contraction of blood vessels, which regulates the tension and diameter of blood vessels, thereby controlling blood pressure and blood flow distribution [40]. Mature VSMC is a non-terminally differentiated cell type with obvious plasticity. The plasticity of VSMCs may depend on environmental cues and changes in extracellular signals perceived by cells.

VSMCs are derived from the mesoderm during embryonic development and gradually differentiate into different cell populations and obtain a differentiated phenotype with adult characteristics, that is, contractile phenotype. However, unlike skeletal muscle and myocardial cells, VSMCs can still be dedifferentiated into a less differentiated secretory type under the stimulation of certain factors after differentiation and maturation [41]. It has been reported that these two phenotypes may represent two extreme types that coexist in a series of different phenotypes in the vascular wall and express different genes and proteins. VSMCs in normal adult arterial vasculature are predominantly constrictive, and their main function is to maintain vascular elasticity and constrict the vasculature [42]. The ability of proliferation and migration of contractile VSMCs is poor or absent. The cell body is spindle-shaped or ribbon-shaped, containing a large number of myofilaments and structural proteins. The content of synthetic organelles such as rough endoplasmic reticulum and Golgi complex is less. The ability of synthetic matrix is poor or absent, and the volume is small. Secretory VSMCs mainly exist in the mid-embryonic blood vessels and pathological blood vessels. Its main functions are proliferation, migration into the intima, and synthesis of ECM proteins. It is similar to fibroblasts in morphology, with less myofilament and structural protein content, more synthetic organelles, stronger ability to synthesize and secrete matrix proteins, and larger volume than contractile type [43].

VSMCs are the main components of the arterial wall, which are usually in a resting state and contribute to vasoconstriction. In the process of vascular injury, SMC dedifferentiates from the resting state to the synthetic state, and the ability of proliferation and migration is enhanced, resulting in intimal hyperplasia. In this process, a variety of signaling pathways are activated, such as AMPK, Akt, ERK, and Wnt/β-catenin signaling pathways, which promote the proliferation and migration of VSMCs [44]. Minimally invasive percutaneous coronary intervention is one of the most common treatments for coronary heart disease, but percutaneous coronary intervention can cause vascular damage, resulting in arterial reocclusion or restenosis [45]. Restenosis is a wound healing response characterized by uninhibited proliferation and migration of SMC and neointimal hyperplasia caused by vascular accumulation of inflammatory cells, which is a major limitation of percutaneous transluminal angioplasty [46]. Similarly, the accumulation of VSMCs is a hallmark of AS [43], which produces a large amount of neointima formed after vascular occlusion or injury [47]. Therefore, a large number of studies are needed to further reduce the stenosis rate caused by neointimal hyperplasia. In summary, the abnormal proliferation and migration of VSMCs leading to neointimal hyperplasia is a core event in the pathophysiology of many cardiovascular diseases, including AS and restenosis after angioplasty.

The Role of TCF21 in the Regulation of SMC Phenotype

Through a multiethnic human genome-wide association study (GWAS), the gene encoding TCF21 is associated with the risk of CAD [48]. TCF21 is necessary for the regulation of SMC phenotype in AS. It promotes the phenotypic transformation of SMCs to fibroblasts, and related studies have also shown that TCF21 can promote the dedifferentiation, proliferation and migration of SMC to the lesion site [3]. It has been previously proposed that TCF21 has a differentiation inhibitory function in skeletal muscle cells, that is, by regulating the expression of p21, the cell cycle is blocked and the differentiation is inhibited, resulting in the precursor cells remaining in an undifferentiated state [49].

Although TCF21 has a significant effect on SMC phenotypic transformation, the mechanism by which it exerts this regulation is still unclear. However, recent studies have found an effective transcriptional coactivator myocardin (MYOCD), which is mainly present in SMCs [50]. MYOCD cannot bind to DNA alone but binds to the more expressed DNA-binding transcription factor serum response factor (SRF) [51]. Cardiomyosin regulates the transcription of cArG-box gene by binding to SRF to form a protein complex, which mainly mediates the differentiation of cardiomyocytes and SMCs. Ectopic expression of MYOCD can activate the expression of SMC differentiation markers such as myosin heavy chain 11 (MYH11), calpain 1 (CNN1), and transgelin (TAGLN) [52, 53]. TCF21, as a transcription factor, is enriched in the genome-wide SRF targeting sites and binds to and inhibits SRF and MYOCD transcriptional activities in SRF and MYOCD sites. TCF21 also prevented the binding of the SRF gene autoregulatory enhancer region to DNA. In addition, the direct interaction between TCF21 and MYOCD destroyed the MYOCD-SRF complex, resulting in a decrease in the MYOCD-SRF association [50]. Therefore, we can conclude that TCF21 regulates the phenotype of SMCs at least in part by antagonizing the MYOCD-SRF pathway through a variety of mechanisms (shown in Fig. 1). These studies have identified a regulatory pathway in SMC that regulates CAD risk, thus providing a possible mechanism for directly inhibiting AS by inhibiting SMC phenotypic regulation [50].

Fig. 1.

TCF21 leads to the development of AS by promoting the abnormal proliferation of neointima and activating the expression of inflammatory genes. On the one hand, TCF21 plays a role in regulating the phenotype of SMCs by antagonizing MYOCD-SRF pathway through various mechanisms, thus promoting the proliferation and migration of SMCs. This leads to abnormal hyperplasia of new intima and eventually leads to lumen stenosis and AS. On the other hand, TCF21 cooperates with AHR to activate the inflammatory gene expression program, which will be aggravated by environmental stimuli such as TCDD, PCB, and PAH, promoting the occurrence and development of AS and possibly leading to the overall risk of coronary heart disease. TCF21, the transcription factor 21; MYOCD, myocardin; SRF, serum response factor; AHR, aryl hydrocarbon receptor; TCDD, dioxins; PCB, polychlorinated biphenyl; PAH, polycyclic aromatic hydrocarbons; VSMC, vascular smooth muscle cell.

Fig. 1.

TCF21 leads to the development of AS by promoting the abnormal proliferation of neointima and activating the expression of inflammatory genes. On the one hand, TCF21 plays a role in regulating the phenotype of SMCs by antagonizing MYOCD-SRF pathway through various mechanisms, thus promoting the proliferation and migration of SMCs. This leads to abnormal hyperplasia of new intima and eventually leads to lumen stenosis and AS. On the other hand, TCF21 cooperates with AHR to activate the inflammatory gene expression program, which will be aggravated by environmental stimuli such as TCDD, PCB, and PAH, promoting the occurrence and development of AS and possibly leading to the overall risk of coronary heart disease. TCF21, the transcription factor 21; MYOCD, myocardin; SRF, serum response factor; AHR, aryl hydrocarbon receptor; TCDD, dioxins; PCB, polychlorinated biphenyl; PAH, polycyclic aromatic hydrocarbons; VSMC, vascular smooth muscle cell.

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TCF21 has been shown to promote the proliferation, migration, and invasion of VSMCs. The unrestricted proliferation of VSMCs will lead to the proliferation of neointima and lead to a series of diseases such as AS, so TCF21 can be a potential therapeutic target for the treatment of a series of cardiovascular diseases caused by arterial thrombosis and lumen stenosis.

Inhibition of Arterial Thrombosis and Stenosis by Targeting TCF21

Recent studies have reported that miR-654-5p is an important gene that regulates VSMC phenotypic transformation. It can inhibit the expression of TCF21 and cell proliferation, invasion, and metastasis [4]. That is, it can inhibit arterial thrombosis and stenosis by targeting TCF21. This provides a strong theoretical basis for TCF21 as a therapeutic target for cardiovascular disease [4]. The proliferation and migration of VSMCs is considered to be a key factor in the development of cardiovascular disease [54, 55]. Recent studies have shown that microRNAs (miRNAs) play an important regulatory role in a variety of cardiovascular and cerebrovascular diseases induced by atherosclerotic plaques [56]. Some miRNAs are considered to be new biomarkers of CAD, and miRNA therapy for CAD has also received a lot of attention [57]. miRNAs are small, siRNA-like molecules that are 22 nucleotides long. MiRNAs are quite conserved in species evolution. MiRNAs found in plants, animals, and fungi are only expressed in specific tissues and developmental stages. MiRNA tissue specificity and timing determine the functional specificity of tissues and cells, indicating that miRNA plays a variety of roles in the regulation of cell growth and development [58]. For example, miR-400a-3p and miR-135b-5p accelerate AS by promoting cell migration and proliferation [55]. MiR-21 has become a new therapeutic target for cardiovascular diseases [59]. MiR-654-5p, a newly studied anti-cancer miRNA, improves prostate, colorectal, breast, and oral squamous cell carcinomas [60‒62]. MiR-654-5p has also been shown to regulate cell migration, cell invasion, and cell proliferation in various cancers [63‒65]. More importantly, MiR-654-5p also plays a key regulatory role in cardiovascular disease, and there is a link between it and TCF21 discussed above. In recent studies, it has been found that miR-654-5p can be expressed in patients with coronary heart disease, and miR-654-5p can inhibit arterial thrombosis and stenosis by targeting TCF21 [4]. MiR-654-5p can inhibit the proliferation, invasion, and migration of SMCs mainly by inhibiting the expression of PDGF-BB. The PDGF family is composed of five proteins: PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. PDGF-BB is reported to be an important stimulator of the proliferation and migration of VSMCs [66, 67]. Previous studies have also mentioned that there is a close relationship between a series of miRNAs and PDGF-BB. For example, miR-328 binds to PIM-1 [68] and miR-638 binds to Nor1 [69]. Both of them inhibit the proliferation and migration of SMCs induced by PDGF-BB in this way. Similarly, miR-654-5p can also bind to related genes to regulate the proliferation and metastasis of various tumors and inhibit the proliferation and migration of TCF21 when miR-654-5p is overexpressed. In summary, we can know that miR-654-5p can inhibit the proliferation, migration, and invasion of VSMCs induced by PDGF-BB by targeting TCF21 and ultimately inhibit the formation of arterial thrombosis and stenosis (shown in Fig. 2). This suggests that TCF21 may become a potential therapeutic target for the treatment of a series of cardiovascular diseases caused by arterial thrombosis and lumen stenosis.

Fig. 2.

Targeting TCF21 by miRNA can reduce lumen stenosis and inflammation to improve AS. On the one hand, miR-654-5p inhibits TCF21 expression by targeting TCF21, regulates PDGF-BB-induced VSMC proliferation and migration, and inhibits arterial thrombosis and stenosis. On the other hand, miR-30-5p can inhibit the inflammatory reaction and cell apoptosis induced by NF-κB signaling pathway and p38 MAPK signaling pathway by targeting TCF21, thus improving atherosclerosis.

Fig. 2.

Targeting TCF21 by miRNA can reduce lumen stenosis and inflammation to improve AS. On the one hand, miR-654-5p inhibits TCF21 expression by targeting TCF21, regulates PDGF-BB-induced VSMC proliferation and migration, and inhibits arterial thrombosis and stenosis. On the other hand, miR-30-5p can inhibit the inflammatory reaction and cell apoptosis induced by NF-κB signaling pathway and p38 MAPK signaling pathway by targeting TCF21, thus improving atherosclerosis.

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On the other hand, more and more evidence shows that TCF21 is a pathogenic gene of coronary heart disease [63‒65, 70], and TCF21 target genes related to coronary heart disease are enriched in the biological process of vascular wall [71]. However, the high expression of TCF21 is associated with a reduced risk of coronary heart disease in human coronary heart disease-related tissues [48]. Related experiments have shown that if TCF21 is specifically knocked out in mouse VSMCs, VSMC phenotypic regulation will be inhibited, and the absence of TCF21 will lead to a decrease in fibroblasts and plaque instability in the lesion, indicating that TCF21 plays a protective role by promoting the transformation of VSMCs into fibroblast-like cells in the lesion and fibrous cap [3, 48]. However, targeting TCF21 also inhibits the proliferation and migration of VSMCs and inhibits arterial thrombosis and stenosis. This indicates that although TCF21 has made significant progress in mapping the genetic contribution of coronary heart disease, the molecular mechanism of TCF21 in cardiovascular disease still has fundamental problems.

TCF21 Can Play a Role in the Activation of Pro-Inflammatory Gene Expression in SMCs

AS is a chronic inflammatory disease, which is an abnormal response of vascular wall to various injuries. Inflammatory response runs through all stages of AS, which may be a common link or pathway in the pathogenesis of various atherosclerotic factors. The mechanism of inflammation is not only related to the occurrence and development of AS but also closely related to the occurrence of various complications of AS. In the early stage of AS, it is mainly characterized by acute exudative inflammation, while in the advanced stage, it is mainly characterized by chronic proliferative inflammation. Inflammatory response involves a variety of inflammatory cells, inflammatory cytokines, inflammatory mediators, adhesion molecules, chemokines, growth factors, and so on. Therefore, inflammation plays an important role in AS.

As mentioned above, TCF21 plays a protective role in coronary heart disease [3]. On the other hand, TCF21 is also believed to contribute to the formation of macrophage-like cells in plaques, promote the inflammatory environment, and destabilize the vascular wall [22, 72, 73]. Therefore, it is not clear whether TCF21 promotes SMC phenotypic regulation to promote or reduce the risk of AS. It also further indicates that the transcription factor TCF21 has two sides. On the one hand, it can play a protective factor role by promoting the transformation of SMC to fibroblast-like cells in lesions and fibrous caps, while on the other hand, TCF21 may have some expression program that activates inflammatory genes, thereby increasing the risk of coronary artery disease.

Recent studies have found that TCF21 and environmental sensor aryl hydrocarbon receptors can synergistically activate pro-inflammatory gene expression programs in coronary artery SMCs. Studies have shown that TCF21 binds to and regulates a CAD-related gene network, and one of the core components of the TCF21 gene network is the aryl hydrocarbon receptor (AHR), a transcription factor that mediates responses to environmental toxins and exogenous substances and can regulate inflammatory cell responses [71, 74, 75]. AHR can bind to a series of complex nuclear proteins, which are involved in different processes related to hormone receptor and inflammatory pathway signal transduction, chromatin remodeling, and activate many target genes, including cytochrome P450 and AHR inhibitor (AHRR) [76, 77]. AHR is highly expressed in the cardiovascular system and plays an important role in cardiovascular development and vascular remodeling [78, 79]. AHR ligands include a wide range of environmental pollutants, such as dioxins (TCDD), coplanar polychlorinated biphenyls, and polycyclic aromatic hydrocarbons (PAH) [79‒81]. Among them, dioxins are associated with an increase in cardiovascular disease mortality [82]. In addition, studies have shown that when AHR binds to ligands with higher affinity, especially ligand dioxins, it will aggravate the occurrence and development of AS [26, 79]. This is due to the activation of AHR-dependent inflammatory mediators and the formation of cholesterol-rich foam cells when macrophages are treated with dioxin, which leads to the development of inflammatory disease AS. The role of AHR in mediating inflammation and AS is to induce vascular inflammation and promote the development of AS by activating the AHR signaling pathway through dioxins [26] (shown in Fig. 1).

It has been found that the transcriptional networks of TCF21 and AHR are overlapping, and the functional role of TCF21 in vascular diseases seems to be closely related to its role in embryonic coronary vascular development. TCF21 is expressed in SMC precursor cells and promotes cell proliferation and migration. AHR is also expressed in the developing coronary circulation, and AHR ligand dioxin can inhibit the development of epicardium and preepicardium in zebrafish [83]. TCF21 promotes the expression of AHR heterodimer partner ARNT AHR and cooperates with these factors to upregulate some inflammatory downstream disease-related genes, including IL1A, MMP1, and CYP1A1. TCF21 binds to AHR, ARNT, and downstream target gene loci, and the binding sites of AHR-ARNT and TCF21 are colocated throughout the genome of HCASMC open chromatin region [84]. These co-localization regions were found to be enriched with GWAS signals associated with cardiac metabolism and chronic inflammatory disease phenotypes. That is to say, TCF21 and AHR work together to activate the gene expression program, which will be aggravated by environmental stimulation, promote the occurrence and development of AS, and may lead to the overall risk of coronary heart disease.

Inhibiting Inflammatory Pathways by Targeting TCF21

A variety of pathways and pathophysiological processes are involved in the occurrence and development of AS, such as inflammation, oxidative stress, and plaque accumulation, as well as NF-κB pathway and TLR4/MAPK pathway [85]. In recent studies, it has been found that miR-30-5p can inhibit the inflammatory response and apoptosis induced by NF-κB signaling pathway and MAPK pathway by targeting TCF21 [86]. MiR-30-5p improves AS by inhibiting apoptosis, promoting cell viability, and reducing ROS accumulation. And studies have shown that miR-30-5p can negatively regulate the expression of TCF21 by inhibiting NF-κB and MAPK signaling pathways to regulate AS. In addition, studies have shown that inhibiting the expression of TCF21 also reduces the expression level of p38. Therefore, it can be explained that miR-30-5p can alleviate AS by reducing the expression level of TCF21. Therefore, the miR-30-5p-TCF21-MAPK/p38 signaling pathway may be a new potential biomarker or therapeutic target for AS [86].

In summary, miR-30-5p can regulate the development of AS by directly targeting TCF21 to inhibit NF-κB and MAPK signaling pathways [87] (shown in Fig. 2). Additionally, it has been found that TCF21 expression is upregulated in calcified atherosclerotic plaques and osteoblast-like VSMCs, and overexpression of TCF21 promotes osteogenic differentiation of VSMCs. And it was found that TCF21 regulates vascular calcification by activating the IL-6-STAT3 signaling pathway [87], sites of chronic inflammation in the vascular system that is the site of AS or media calcification [88‒90]. Not only that TCF21 exacerbated inflammatory cytokine production in endothelial cells but also reduced IL-6 production when TCF21 was knocked down in ECs [87]. This suggests that TCF21 promotes the interaction between ECs and VSMCs through the production of inflammatory cytokines. Inhibition of TCF21 expression could therefore serve as a new potential therapeutic target for the prevention and treatment of a range of cardiovascular diseases triggered by inflammatory responses.

Atrial fibrillation, abbreviated as AF, is a common cardiac arrhythmia, which is a severe disturbance of the electrical activity of the atria, with loss of regular and orderly electrical activity of the atria, replaced by rapid and disorderly fibrillation waves. It is usually characterized by an irregular and rapid heart rate [91, 92]. AF not only affects the patient’s quality of life but can also lead to complications such as thromboembolism and heart failure, with the most serious complication being stroke [93]. Since pulmonary vein trigger is a common trigger for AF, radiofrequency ablation is the main method to control AF, especially for patients with drug-refractory paroxysmal atrial fibrillation (PAF) [94]. However, the recurrence rate is still high after radiofrequency ablation. In a recent study, it was found that the G allele and GG genotype of rs12190287 in TCF21 and the increase of TCF21 concentration were significantly associated with the occurrence of PAF and recurrence after ablation. TCF21 rs12190287 polymorphism can regulate the expression of TCF21, and the G allele and GG genotype of rs12190287 are associated with the pathogenesis and recurrence of PAF [95]. This suggests that TCF21 rs12190287 polymorphism may be a potential marker of genetic susceptibility to PAF onset and recurrence after catheter ablation in the Chinese population.

Hypertension is a systemic disease mainly characterized by a sustained increase in systolic and/or diastolic blood pressure in the arteries of the body, for hypertensive patients, due to prolonged periods of high blood pressure, it can damage the endothelium of the blood vessels, making it easier for lipids to be deposited in the walls of the coronary arteries, accelerating coronary AS, leading to a sustained increase in the incidence of coronary heart disease, and it can lead to the sustained thickening of the walls of the coronary arteries, with a gradual narrowing of the lumen, causing angina pectoris to occur more frequently, and even leading to myocardial infarction. Many studies have shown that TCF21 rs12190287 is also a susceptibility site for hypertension in the Japanese population [96]. The polymorphism of TCF21 rs76987554 is also significantly correlated with hypertension [97]. Previous studies have shown that TCF21 can reduce the expression of cyclin-dependent kinase inhibitor P21 in MG63 cells, which is essential for the proliferation of VSMCs, and microvascular stenosis caused by abnormal proliferation may play a key role in the development of hypertension [98]. This suggests that TCF21 may regulate blood pressure through P21-dependent microvascular remodeling.

This review focuses on the role of TCF21 in cardiovascular diseases. On the one hand, the abnormal proliferation and migration of VSMCs promotes the proliferation of neointima, and the proliferation of neointima will cause lumen stenosis, which will finally lead to a series of diseases such as AS and postoperative restenosis. TCF21 is expressed in the precursor cells of SMCs and is involved in regulating the phenotypic transformation of VSMCs to enhance the proliferation and migration of VSMCs. Therefore, it seems to be a feasible treatment to inhibit the proliferation, migration, and invasion of VSMCs by targeting TCF21 to reduce arterial thrombosis and lumen stenosis. As mentioned above, miR-654-5p can inhibit arterial thrombosis and stenosis by targeting TCF21 and alleviate the occurrence and development of AS. On the other hand, TCF21 can activate the expression of inflammatory genes by promoting the expression of aryl hydrocarbon receptors, which ultimately leads to an increased risk of coronary artery disease, indicating that TCF21 is closely related to inflammation. In recent studies, it has been found that targeting TCF21 by miR-30-5p can inhibit the inflammatory response and apoptosis induced by NF-κB signaling pathway and MAPK pathway, which helps alleviate the occurrence of AS. Through the above description, it is not difficult to find that targeting TCF21 seems to be an important way to improve cardiovascular diseases. However, TCF21 also plays an important role in the development of normal tissues and organs, especially in the cardiovascular system. For example, the progenitor cell pool of transcription factors such as TCF21 is an important supplement to the first and second heart regions during heart development and is therefore also considered to be the third heart region of the heart. Epicardial progenitor cells play an indispensable role in cardiac development and angiogenesis.

It seems that TCF21 has two sides. The current challenge is to regulate the expression and activity of TCF21 under specific pathological conditions, which will require accurate information on the regulation and activity of TCF21 in health and cardiovascular diseases.

The authors have no conflicts of interest to declare.

This study was supported by the National Natural Science Foundation of China (82100789), the Natural Science Foundation of Hunan Province (2022JJ40378), the Scientific Research Foundation for Doctor of University of South China (200XQD060), the Natural Science Foundation of Hunan Province (2023JJ40563), and the College Students’ Innovation and Entrepreneurship Training Program (S202112650009).

Yaqian Luo and Ji Huang performed the literature review. Yaqian Luo drafted most of the manuscript and critically revised it in its entirety. Fangzhou He, Yifang Zhang, Shufan Li, Ruirui Lu, and Xing Wei revised it in its entirety. Ji Huang is responsible for ensuring that the descriptions are accurate and agreed upon by all authors. Credit in no way changes the journal’s qualification criteria for authorship.

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