Transient inflammation and its resolution after vascular injury are necessary for wound healing and repair, whereas prolonged excessive inflammation leads to pathological vascular remodeling manifested as neointimal hyperplasia (72). Among other things, vascular inflammation induces endothelial dysfunction and confers a pro-adhesive and pro-thrombotic phenotype to endothelial cells, which has a significant effect on the development and progression of various CVDs, most notably AS, thrombosis and congestive HF (73). Vascular remodeling is a complex pathological process that is a fundamental pathological process characterized by abnormal changes in vascular cell morphology, structure and function in various diseases, such as migration, proliferation, hypertrophy and apoptosis and is mostly caused by vascular endothelial injury, medial smooth muscle proliferation, extracellular matrix remodeling, oxidative stress and vascular inflammation, which in turn leads to increased vascular tone and thus the development of vascular disease (74,75). Currently, studies have confirmed that the role of ETS factors in regulating endothelial-specific gene expression (76-78) and studies support a role for several ETS family members in the regulation of vascular inflammation and vascular remodeling, including endothelial activation in response to inflammatory mediators, recruitment of inflammatory cells to the vascular wall and proliferation and migration of vascular smooth muscle cells (VSMCs) (79-81) (Fig. 3).

Angiotensin II (Ang II) is a central mediator of vascular inflammation and remodeling and Zhan et al (82) found in vascular smooth muscle and endothelial cells from mouse thoracic aorta that the transcription factor ETS-1 was rapidly induced in response to systemic Ang II infusion and that compared with control mice, ETS-1^−/− mice had markedly reduced arterial wall thickening, perivascular fibrosis and cardiac hypertrophy. Also, cell cycle-dependent kinase inhibitor p21CIP (associated with cell hypertrophy, cell cycle arrest, apoptosis and endothelial dysfunction), plasminogen activator inhibitor-1 (PAI-1; which promotes the development of perivascular fibrosis) and monocyte chemotactic protein-1 (MCP-1; a central mediator of inflammatory responses in hypertensive vascular disease) were identified in the study as ETS-1 targets, all of which were reduced in expression in ETS-1^−/− mice in response to Ang II and resulted in a significant reduction in T cell and macrophage recruitment to the vessel wall compared with control mice. This suggests that ETS-1 plays a key role in Ang II-induced vascular inflammation and remodeling. Vascular inflammation plays an important role in the pathogenesis of hypertension, atherosclerosis, restenosis and other forms of vascular disease. In particular, carotid balloon injury is a model of vascular injury characterized by increased expression of inflammatory mediators and marked leukocyte infiltration, which leads to a process of vascular remodeling and neointimal formation after luminal injury (83,84). Feng et al (85) found that the expression of ETS-1 was markedly increased after balloon injury, which mediated the increased expression of pro-inflammatory molecules and adhesion molecules in carotid balloon injury, including MCP-1, P-selectin and E-selectin and that the blockade of ETS-1 before balloon injury not only reduced leukocyte infiltration but also prevented the development of neointima after balloon injury. Taken together, ETS-1 plays a key role as a transcriptional mediator of inflammation and neointima formation induced by intraluminal vascular injury and has the potential to be a new strategy for the treatment and prevention of diseases associated with vascular injury.

Angiogenesis is a complex event that requires endothelial cell germination, lumen formation and tubulogenesis and is regulated by the coordinated action of different transcription factors. Angiogenesis is involved in a variety of biological processes, including atherosclerosis and cancer. Many transcription factors have been implicated in vascular development and angiogenesis and their interactions lead to endothelial cell differentiation and the acquisition of arterial, venous and lymphatic properties (86). For example, Di et al (87) found that miR33a-5p/ETS-1/Dickkopf1 (DKK1) signaling was pro-angiogenic in ox-LDL-induced HUVECs.

Endothelial cells (ECs) are located in the innermost layer of blood vessels and form the vascular lining, which is important for maintaining vascular homeostasis and normal circulation (88). In response to endothelial dysfunction caused by stimulation by pathological (hyperbaric or hypoxic) and chemical (oxidized low-density lipoprotein or infection) factors, ECs are activated, increasing their permeability, releasing cytokines to promote inflammation and thrombosis and increasing adhesion molecule recruitment and adhesion to inflammatory factors (89). Endothelial dysfunction and endothelial activation are thought to play a key role in the initiation of the atherosclerotic process and the progression of advanced AS (90). AS is a chronic vascular inflammatory disease and is one of the leading causes of cardiovascular morbidity and mortality (91). The development of AS is associated with structural vascular lesions and the pathologic process involves endothelial damage, lipid deposition, inflammatory cell infiltration, foam cell formation and plaque formation, leading to the formation of atherosclerotic plaques (92). These plaques narrow the lumen of the coronary arteries, leading to episodic or persistent angina. If the plaque ruptures, it can lead to thrombus formation, myocardial infarction and even death (93). AS involves complex interactions between various cell types, including macrophages, ECs and smooth muscle cells (SMC) (94). AS is a complex disease involving multiple factors. Currently, it has been demonstrated that ETS-1/ETS-2 plays a role in the regulation of vascular inflammation in AS, including endothelial activation in response to inflammatory mediators, recruitment of inflammatory cells to the vascular wall and proliferation and migration of VSMCs (79). ETS-1 is upregulated in vitro upon exposure to agonists such as serum and is expressed in damaged vessels and it is also expressed in SMCs in human carotid atherosclerotic lesions (95). Similarly, it has been shown that in ApoE^−/− mice experiments using a vulnerable plaque model, ETS-2 expression is increased under atherogenic conditions and is specifically enhanced in vulnerable plaques compared to stable plaques. ETS-2 levels are associated with microvessel formation within the plaque and proinflammatory in human vulnerable atherosclerotic plaques ETS-2 levels correlate with intraplaque microvessel formation and proinflammatory cytokine levels in human susceptible atherosclerotic plaques and overexpression of ETS-2 promotes lesion growth with neovascularization, hemorrhage and plaque destabilization (96).

Currently, it has been shown that ETS-2 is critical for a variety of inflammatory functions in human macrophages and that macrophage activation, cytokine production, reactive oxygen species (ROS) production, phagocytosis and migration are induced by overexpression of ETS-2 in a dose-dependent manner and that overexpression of ETS-2 increases the secretion of pro-inflammatory cytokines. RNA sequencing of ETS-2 edited and unedited inflammatory macrophages from multiple donors reveals that disruption of ETS-2 results in extensive transcriptional changes and reduced expression of many inflammatory genes. This suggests that macrophage ETS-2 signaling may play a central role in a variety of inflammatory diseases (97). Moreover, Jiang et al (80) found that ETS-1 promotes hyperglycemia-mediated endothelial inflammation by upregulating protein tyrosine phosphatase 1B (PTP1B) expression, which is involved in high glucose-induced elevation of endothelial cell inflammatory factor levels). In addition, it was found that hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and ETS-1 coexist in the deeper layers of plaques in carotid atherosclerosis, with significant angiogenesis. Notably, the major lesions of plaques exhibit markedly elevated levels of HIF-1α, VEGF and ETS-1. This suggests that HIF-1α induces angiogenesis through the expression of VEGF and ETS-1 (98). In addition, Katsume et al (99) also found that the early inflammatory response in atherosclerosis is mediated by proline-rich tyrosine kinase/reactive oxygen species, which induces the release of tumor necrosis factor α (TNF-α) and promotes the expression of TNF-α-dependent pro-inflammatory molecules through the p21^Cip1/ETS-1/p300 transcriptional regulatory system. Endothelial dysfunction represents the initial step of AS. Endothelial dysfunction is the initial step of AS (100). 17β-estradiol (E2) can delay atherosclerosis formation by improving lipid levels, accelerating endothelial repair by promoting endothelial proliferation and migration, inhibiting the proliferation and migration of vascular smooth muscle cells and modulating the function of immune cells to alleviate the vascular inflammatory response (101-103). Li et al (104) demonstrated the effect of E2 on miR-126-3p expression (which is critical in the proliferation, migration and tube formation) in a cellular model by utilizing human venous umbilical cord endothelial cells. Using human venous umbilical cord endothelial cells, Li et al (104) demonstrated the effect of E2 on microRNA (miRNA/miR) 126-3p expression (which plays a critical role in endothelial cell proliferation, migration and tube formation), which prevents endothelial cell apoptosis and slows down atherogenesis in a cellular model and identified the key role of ETS-1, a transcription factor for miR-126-3p. It was found that E2 increased the expression level of miR-126 through ETS-1 in HUVEC and then miR-126-3p bound to its targets Spred1 and vascular cell adhesion molecule-1 (VCAM-1) mRNA, leading to their degradation and silencing of protein expression and finally promoted endothelial proliferation, atherogenesis and atherosclerosis. In addition, Nie et al (105) showed that the ETS-2 transcription factor is a potent regulator of angiogenesis and mediates immune activation of the endothelium in the late stages of AS. miR-203 promotes the proliferation of vascular smooth muscle cells and was found to be involved in the process of atherosclerotic plaque formation through the regulation of ETS-2. Immediately after, Nie et al (105) found that shangou, a common traditional aromatic herb, reduced atherosclerotic plaque area and serum antioxidant low-density lipoprotein (LDL) autoantibodies in endogenous high angiotensin II ApoE^−/− mice by increasing miR-203 expression and decreasing ETS-2 expression, which was beneficial in preventing or treating the onset and progression of AS. In addition, it has been demonstrated that tyrosine kinase receptor B (TrkB) plays an important role in protecting the integrity of the endothelial barrier during the process of atherogenesis and Jiang et al (106) found that TrkB can promote VE-calmodulin expression in endothelial cells by inducing and activating the expression of ETS-1, which binds to two ETS binding sites in the promoter of the VE-calmodulin gene in endothelial cells. ETS-1 promotes VE- cadherin expression by binding to two ETS binding sites in the VE- cadherin promoter in endothelial cells to protect endothelial integrity during atherogenesis.

Inflammation is observed in all stages of atherosclerosis, the initial phase of which is characterized by leukocyte recruitment to activated ECs. Zhu et al (107) used bioinformatics analysis to show that ETS-1 is a key endothelial transcription factor in inflammation and tube formation and is a candidate target for the miR-155 and miR-221/222 clusters and that miR-155 and miR-221 are highly expressed in human umbilical vein endothelial cells (HUVECs) and VSMCs, confirming that angiotensin II type 1 receptor (AT1R) is a target of miR-155 in HUVECs. It was found that HUVEC with high miR-155 expression may co-target AT1R and ETS-1, while miR-221/222 targets ETS-1, which indirectly regulates the expression of several inflammatory molecules in ECs, thereby attenuating the adhesion of Jurkat T-cells to activated HUVECs and decreasing the migration of HUVECs and thus reducing the inflammation of endothelial cells and ameliorating atherosclerosis.

Ischemic heart disease has become the leading cause of morbidity and mortality worldwide (108). Myocardial cell death plays a central role in the pathogenesis of ischemic heart disease; therefore, timely restoration of coronary blood flow, that is, reperfusion, is the best method to reduce myocardial cell loss induced by ischemic injury (109). However, myocardial reperfusion can lead to further damage to the heart, termed MIRI (110). MIRI leads to myocardial dysfunction, cardiomyocyte loss and fibrosis. The process of myocardial ischemia/reperfusion can lead to several types of cardiomyocyte death, including necrosis, apoptosis, autophagy and iron death (111). These new forms of regulated cell death lead to cardiomyocyte loss and exacerbate MIRI by influencing ROS production, calcium stress and inflammatory cascade responses, which subsequently mediate adverse remodeling, cardiac insufficiency and HF. Therefore, prevention of cardiac apoptosis and fibrosis has been the goal of some therapies that interfere with MIRI.

Lee et al (112) found that adipose-derived stem cell conditioned medium (ADSC-CM) had a significant effect on apoptosis and fibrosis in MIRI-treated hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes. ADSC-CM attenuates cardiac apoptosis and fibrosis by downregulating the expression of p53 upregulated modulator of apoptosis (PUMA) and ETS-1 via the miR-221/222/p38/NF-κB pathway, thereby alleviating MIRI. The approximate mechanisms are as follows:

ADSC-CM treatment markedly reduced the expression of apoptosis-related proteins, such as PUMA, phosphorylated (p-)p53 and B-cell lymphoma 2 (Bcl2), as well as the fibrosis-related proteins, ETS-1, fibronectin and collagen 3, and markedly attenuated the cardiac injury and fibrosis in both MIRI-treated mice and H/R-treated cardiomyocytes.

Apoptosis, ROS and inflammation-induced myocardial injury are the most critical factors in MIRI (114). It has been demonstrated that the lysine (K)-specific demethylase 3A (KDM3A), plays a key role in MIRI. Guo et al (115) found that KDM3A knockdown exacerbated myocardial dysfunction and cardiomyocyte injury in vivo and in vitro, while worsening mitochondrial apoptosis, ROS and inflammation were observed. By contrast, KDM3A overexpression was ameliorated in MIRI. At the same time, it was found that KDM3A, which is known to target ETS-1, directly regulates ETS-1 expression by binding to its promoter region. KDM3A overexpression leads to higher ETS-1 transcription, resulting in reduced apoptosis, ROS and inflammation, which plays a protective role during myocardial injury. Thus, the data from this study suggest that the protective effect of KDM3A on MIRI is partially attributable to epigenetic transactivation of ETS-1.

Thus, it is clear that targeting ETS-1 plays a critical role in preventing MIRI-induced apoptosis and hypertrophy. However, there is no experimental data to analyze whether ETS-2 can prevent MIRI through certain mechanisms.

Cardiac remodeling, defined as genomic, molecular, cellular and interstitial alterations clinically manifested as changes in cardiac size, shape and function in response to cardiovascular injury and pathogenic risk factors, is at the core of most CVD and persistent cardiac remodeling almost always ends in HF and mortality (116). Cardiac remodeling is categorized as physiological (in response to growth, exercise and pregnancy) and pathological (in response to inflammation, ischemia, MIRI, biomechanical stress, excessive neurohormonal activation and pressure overload). Among these, pathological cardiac remodeling is the process of structural and functional changes in the left ventricle as a result of internal or external cardiovascular injury or pathogenic risk factors (117,118). Pathological changes in pathological cardiac remodeling include cardiomyocyte apoptosis, cardiac hypertrophy and cardiac fibrosis and persistent adverse remodeling can lead to HF (119,120). Therefore, it is crucial to understand the mechanisms leading to cardiac remodeling and to prevent adverse remodeling. Research has demonstrated the critical role of ETS-1/ETS-2 in the development of cardiac remodeling.

The process of diabetic cardiomyopathy involves a series of sequential and interrelated steps, including myocardial apoptosis, hypertrophy and fibrosis. Cardiomyocyte apoptosis is key to this process and to myocardial remodeling. Wang et al (121) found that elevated levels of high mobility group box 1 (HMGB1) may promote cardiomyocyte apoptosis induced by high glucose (HG) or hyperglycemia. HG can activate ETS-1; however, inhibition of HMGB1 can attenuate HG-induced ETS-1 activation through ERK1/2. However, inhibition of HMGB1 attenuates HG-induced ETS-1 activation through ERK1/2 signaling. In addition, inhibition of ETS-1 markedly reduces HG-induced cardiomyocyte apoptosis. In conclusion, inhibition of HMGB1 may prevent HG-induced cardiomyocyte apoptosis by downregulating ERK-dependent activation of ETS-1.

The two major cellular signaling pathways that drive cardiac hypertrophy are the calcineurin/nuclear factor of activated T-cells (NFAT) pathway and the MAPK/ERK pathway and sustained activation of either of these pathways causes myocardial hypertrophy (122,123). Luo et al (124) found that ETS-2 is activated during hypertrophic myocardial growth, and ETS-2 deficiency attenuates cardiac hypertrophy induced by pressure overload. In addition to this, ETS-2 was observed to be activated by Erk1/2 in hypertrophic mouse hearts and in human dilated cardiomyopathy tissues in this study. ETS-2 is also required for pressure overload and calmodulin-induced cardiac hypertrophy and, as a transcription factor, ETS-2 is able to bind to the promoters of hypertrophic hallmark genes, such as atrial natriuretic peptide, brain natriuretic peptide and Rcan1.4, which is an established downstream target of NFAT. ETS-2 forms a complex with NFAT, stimulating transcriptional activity by enhancing NFAT binding to the promoters of at least two hypertrophy-stimulating genes: Rcan1.4 and miR-223 (which are downstream targets of ETS-2 and NFAT in cardiomyocytes). Inhibiting miR-223 in cardiomyocytes suppresses calcineurin-mediated cardiac hypertrophy, revealing that microRNA-223 is a novel pro-hypertrophic target of the calcineurin/NFAT and Erk1/2-ETS-2 pathways. In conclusion, ETS-2 plays a critical role in cardiac hypertrophy driven by the calmodulin/NFAT pathway and reveals a molecular link between the Erk1/2 activation of ETS-2 and the expression of NFAT/ETS-2 target genes. Furthermore, Zhan et al (82) demonstrated that ETS-1 is a key mediator of vascular remodeling and inflammation in response to Ang II. The authors showed that vascular proliferation, perivascular fibrosis and cardiac hypertrophy, were markedly reduced in ETS-1^−/− mice in response to systemic administration of Ang II compared to control mice.

ETS-1, as a prototypical member of the ETS family of transcription factors, has now been demonstrated in several studies to play an important role in myocardial fibrosis. Hao et al (125) identified a role for ETS-1 in the pro-fibrotic effects of Ang II in cardiac fibroblasts (CFs) and in the heart in vivo. In the left ventricle of Ang II-infused rats, ETS-1, plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) protein levels were concomitantly upregulated, while activation of ERK and c-Jun NH2-terminal kinase was increased. Knockdown of ETS-1 by short interfering RNA markedly inhibits the induction of cell proliferation and CTGF and PAI-1 expression by Ang II. Thus, ETS-1 may mediate Ang II-induced cardiac fibrotic effects. These findings point for the first time to the potential role of ETS-1 in cardiac fibrosis in vitro and in vivo, contributing to a fundamental understanding of the molecular mechanisms underlying myocardial fibrosis as a pathological process and laying the foundation for further studies. Subsequently, it was suggested that endothelial-mesenchymal transition (EMT) promotes Ang II-mediated cardiac fibrosis and that ETS-1 has a potential role in Ang II-mediated myocardial fibrosis. Xu et al (126) found that endothelial ETS-1-deficient mice exhibited markedly reduced cardiac fibrosis and hypertrophy after Ang II infusion, accompanied by decreased expression of fibrotic stromal genes, EMT (which is a possible source of myofibroblasts and has been shown to cause myocardial fibrosis) as well as its downstream transcription factors (including Snail family transcriptional repressor 1, Snail family transcriptional repressor 2, Twist-related protein 1 and Zinc finger E-box binding homeobox 1), as well as reduced expression of cardiac hypertrophy and hypertrophy-related genes. Moreover, in vitro studies using cultured H5V cells further demonstrated that ETS-1 knockdown inhibited TGF-β1-induced EMT. Thus, it is evident that deletion of endothelial ETS-1 attenuates Ang II-induced myocardial fibrosis through inhibition of EMT and that inhibition of ETS-1 may be a potential therapeutic strategy for delaying myocardial fibrosis.

Aldosterone plays an important role in the pathophysiology of cardiac remodeling and recently, spironolactone (an aldosterone receptor antagonist) has been found to improve cardiac structure, function and prognosis and delay the progression of myocardial fibrosis in patients with HF. Wang et al (127) found that spironolactone reduced the levels of inflammatory cytokines in the myocardial tissues of autoimmune myocarditis (EAM) and had a positive effect on experimental myocardial fibrosis in EAM mice. This study found that ETS-1 was activated through the TGF-β1/Smad-2/3 signaling pathway and is involved in EAM-induced cardiac fibrosis in EAM mice and the use of spironolactone markedly inhibited the activation of ETS-1 and the phosphorylation of TGF-β1/Smad2/3 and suppressed ETS-1-mediated myocarditis-induced myocardial fibrosis. In addition, inhibition of ETS-1 also reduced the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 in EAM mice, which reduced myocardial fibrosis. The results of this study suggest that the improvement of myocardial fibrosis by spironolactone may be related to the TGF-β1/Smad-2/3/ETS-1 signaling pathway in EAM mice.

In addition, abnormal levels of chitinase-3-like protein 1 (CH3L1) and long non-coding RNA (lnc)TUG1 are associated with myocardial fibrosis. Sun et al (128) found that CH3L1 upregulated the expression of lncTUG1 and lncTUG1 weakened the inhibitory effect on ETS-1 through sponge adsorption of miR -495-3p, which promoted the process of myocardial fibrosis. Similarly, Li et al (129) isolated exosomes from MSC and administered them in vitro to CFs and male infarcted Sprague-Dawley rat hearts in vivo with vericiguat-treated mesenchymal stem cell-derived exosomes (MSCVER-Exos) and found that MSCVER-Exo was able to inhibit the proliferation of CFs. MSCVER-Exo was found to inhibit CFs proliferation, migration and pro-fibrotic gene expression. Meanwhile, miR-1180-3p was found to be enriched in MSCVER-Exo and ETS-1 was a downstream target of miR-1180-3p. miR-1180-3p could be delivered to CFs through Exo and attenuate TGF-β1-induced fibrosis by inhibiting ETS-1 signaling. Thus, miR-1180-3p targeting ETS-1 plays an important role in anti-fibrosis.

JS is a rare syndrome caused by partial chromosomal deletions in the 11q23 region between sub-band 11q23.3 and telomeres, ranging from approximately 7 Mb to 20 Mb (130). The condition was first described in 1973 by Dr Jacobsen, in which multiple members of a family inherited an unbalanced 11;21 translocation from parents who carried a balanced translocation chromosome (131). Since Jacobsen's first report, more than 200 cases have been noted (132). In cases of JS diagnosed after birth in the neonatal period, the majority of children with JS have prolonged hospitalizations, most commonly due to feeding difficulties, heart problems, or bleeding problems. Of these children, ~20% succumb within the first two years of life, most commonly related to complications of congenital heart disease, most of which require surgical intervention. Of patients with heart defects, ~1/3 have membranous ventricular septal defects, another third have left ventricular outflow tract defects with varying degrees of hypoplasia or obstruction of the mitral valve, left ventricle, aortic valve, or aorta and the final third present with a variety of heart defects, including right ventricular double outlet, transposition of the great arteries, atrioventricular septal defect, ostium secundum atrial septal defect, dextrocardia, anomalous right subclavian artery, patent ductus arteriosus, persistent left superior vena cava, tricuspid atresia, interrupted aortic arch type B, persistent truncus arteriosus and pulmonary valve stenosis (133,134). It has been shown that ETS-1 transcription factors play an important role in mammalian heart development, thus providing important insights into some of the most common congenital heart diseases. For example, Ye et al (135) identified an ~7 megabase (Mb) cardiac critical region distal to the long arm of chromosome 11 that contained a gene for congenital heart disease, ETS-1, which is a candidate for causing congenital heart disease in at least some of the patients with 11q- JS. In addition, phenotypic analysis of gene-targeted ETS-1 KO mice by Ye et al (135) showed that deletion of ETS-1 in a pure C57/B6 background resulted in a high prevalence of ectopic, large membranous ventricular septal defects and frequently abnormal ventricular morphology characterized by a bifid apex. Thus, in summary, these results suggest a role for ETS-1 in ventricular development and a gene in the critical region of Jacobsen syndrome, the deletion of which leads to ventricular septal defects and abnormal ventricular morphology in mice.

Ventricular septal defects, including double outlet right ventricle, are one of the most common congenital heart diseases (CHDs) in JS. One possible mechanism for CHDs and other problems in Jacobsen syndrome is a defective function of neural crest cells (cNCCs), which are required for normal mouse cardiac development to accurately regulate the differentiation of cNCCs. Ye et al (136) again found that ETS-1 is strongly expressed in mouse cNCCs and that the expression of Sox10, a key regulator of the gene regulatory network of neural crest cells and an early marker of NCCs, helps to analyze the function of cNCCs during embryonic development. However, this study found that deletion of ETS-1 leads to a decrease in migrating cells expressing Sox10 in E10.5 C57/B6 mouse embryos, which results in impaired cardiac NCC function and causes congenital heart defects.

HF has become a rapidly growing global health problem affecting more than 37.7 million people worldwide. The prevalence of HF has been increasing in this decade as the population over the age of 65 increases (137). Although many different approaches have been investigated to help manage HF, including medical devices, medications and telemonitoring, the clinical management of HF remains relatively poor (138). Therefore, there is an urgent need for clinicians to investigate new therapies for the treatment of HF.

Dysregulation of gene expression is a common mechanism in HF and transcription factors (TFs) are thought to play an important role in the regulation of gene expression. Li et al (139) analyzed the expression levels of miR-155, G protein-coupled receptor 18 (GRP18) and ETS-2 in clinical HF samples through the use of bioinformatics and experimental analysis and functional validation was performed in H9c2 cells. A total of three miRNAs and eight TFs were identified in the TF/miRNA target network. clinical validation showed that the expression level of miR-155 was markedly reduced in HF samples, whereas the expression levels of ETS-2 and GPR18 were markedly increased in HF samples and GPR18 was found to be targeted by both ETS-2 and miR-155. Thus, the data suggest that miR-155 and ETS-2 may play a key role in the development of HF by targeting GPR18 and this finding may help to provide new information for understanding and treating HF. In addition to this, Tan et al (140) found that ETS-2 could promote cardiomyocyte apoptosis and autophagy in HF by regulating the lncRNA TUG1/miR-129-5p/ATG7 axis. In this experiment, it was found that H₂O₂ stimulation increased the expression of ETS-2, TUG1 and ATG7 and decreased the expression of miR-129-5p in AC16 cells, which stimulated cardiomyocyte apoptosis and autophagy, whereas the absence of ETS-2, the silencing of TUG1, or the upregulation of miR-129-5p reversed this phenomenon.

DNA methyltransferase 1 (DNMT1) expression is rapidly upregulated in cardiac tissues of mice with pressure overload and adriamycin-induced HF, which promotes the development of HF (141). In addition to this, dysregulation of mitochondrial autophagy has been associated with the progression of HF and aging (142). Deng et al (143) pointed out that upregulation of miR-152-3p plays a protective role in cardiomyocytes and the STRING database predicted that there is an interaction between ETS-1 and Ras homologous gene family member H (RhoH) and that ETS-1/RhoH may inhibit mitochondrial autophagy and exacerbate HF. Therefore, targeting the ETS-1/RhoH axis may be a potential therapeutic approach. Meanwhile, Deng et al (143) found that DNMT1 may inhibit miR-152-3p expression by promoting the methylation of miR-152-3p and enhancing the expression of ETS-1, which induces RHOH transcriptional activation and inhibits mitochondrial autophagy and ultimately promotes the development of HF.