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Administration of EGFR inhibitors blocked EGFR signaling activation in HFD-fed ApoE −/− mouse artery. (a) The structures of AG1478 and compound 542. ApoE −/− mice were fed with HFD for 8 weeks, and treated with AG1478 (AG, 10 mg/kg/day) or 542 (10 mg/kg/day) for 8 weeks by oral gavage. (b,c) Serum levels of LDL and TG. (d) Representative microscopic images of EGFR and p-EGFR immunochemical staining in artery tissues. (e) Western blot analysis of p-EGFR, p-AKT and p-ERK in artery tissues, with the densitometric quantifications shown in Supplementary Fig. S3. The gels were run under the same experimental conditions. Shown are cropped gels/blots (The gels/blots with indicated cropping lines are shown in the Supplementary Fig. 20). (LFD = low fat diet, HFD = high fat diet; n = 7 in each group; ## P < 0.01, vs LFD; ns, not significant vs HFD). The quantification results for all staining images were shown in the Supplementary File.
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Atherosclerosis is a progressive disease leading to loss of vascular homeostasis and entails fibrosis, macrophage foam cell formation, and smooth muscle cell proliferation. Recent studies have reported that epidermal growth factor receptor (EGFR) is involved vascular pathophysiology and in the regulation of oxidative stress in macrophages. Although...
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... We first wanted to know if inhibiting EGFR alters serum lipid levels since elevated low-density lipoproteins (LDL) have been shown to be strongly related to the development of atherosclerosis. ApoE −/− mice fed a high fat diet (HFD) exhibited increased serum levels of LDL and triglycerides (TG) as compared to mice fed a control/low fat diet (LFD) (Fig. 1b). We also tested the serum insulin level and found that HFD induced the increase in serum insulin while AG or 542 did not affect the insulin level ( Supplementary Fig. S1). Inhibiting EGFR through 542 or AG1478 for 8 weeks showed no significant differences in the levels of serum lipids between the HFD mice and the treated groups (Fig. ...
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... −/− mice fed a high fat diet (HFD) exhibited increased serum levels of LDL and triglycerides (TG) as compared to mice fed a control/low fat diet (LFD) (Fig. 1b). We also tested the serum insulin level and found that HFD induced the increase in serum insulin while AG or 542 did not affect the insulin level ( Supplementary Fig. S1). Inhibiting EGFR through 542 or AG1478 for 8 weeks showed no significant differences in the levels of serum lipids between the HFD mice and the treated groups (Fig. 1b,c). ...
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... (LFD) (Fig. 1b). We also tested the serum insulin level and found that HFD induced the increase in serum insulin while AG or 542 did not affect the insulin level ( Supplementary Fig. S1). Inhibiting EGFR through 542 or AG1478 for 8 weeks showed no significant differences in the levels of serum lipids between the HFD mice and the treated groups (Fig. 1b,c). Examination of aorta tissues by immunohistochemistry showed increased levels of EGFR expression and phos- phorylation in HFD-fed mice compared to LFD-fed mice ( Fig. 1d and Supplementary Fig. S2). Interestingly, treatment of mice with 542 and AG1478 reduced the levels of p-EGFR immunoreactivity but not total EGFR. We also noted ...
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... Fig. S1). Inhibiting EGFR through 542 or AG1478 for 8 weeks showed no significant differences in the levels of serum lipids between the HFD mice and the treated groups (Fig. 1b,c). Examination of aorta tissues by immunohistochemistry showed increased levels of EGFR expression and phos- phorylation in HFD-fed mice compared to LFD-fed mice ( Fig. 1d and Supplementary Fig. S2). Interestingly, treatment of mice with 542 and AG1478 reduced the levels of p-EGFR immunoreactivity but not total EGFR. We also noted activation of predominant signaling proteins downstream of EGFR, namely extracellular signal-reg- ulated kinase (ERK) and Akt. Immunofluorescent staining analysis for p-ERK and ...
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... signal-reg- ulated kinase (ERK) and Akt. Immunofluorescent staining analysis for p-ERK and p-AKT in aorta tissues found that administration with EGFR inhibitors significantly blocked HFD-induced ERK and Akt phosphorylation in aortas of ApoE −/− mice (Supplementary Fig. S3a-d). Proteins isolated from aorta tissues confirmed these results ( Fig. 1e and Supplementary Fig. S4a-d). These results show increased EGFR phosphorylation and activity in atherosclerotic lesions in ...
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... that EGFR inhibitors 452 and AG1478 are able to attenuate atherosclerosis through reducing inflammation in mice, we investigated the anti-inflammatory effects of EGFR inhibitors in oxidized-LDL (ox-LDL)-stimulated primary macrophages. Brief exposure of macrophages to ox-LDL induced EGFR phosphorylation, but not EGFR expres- sion, as detected by western bott method ( Fig. 4a and Supplementary Fig. S9) and immunofluorescence staining ( Fig. 4b and Supplementary Fig. S10). The levels of p-EGFR were greatly reduced when cells were pre-treatment with 542 or AG1478 ( Fig. 4b and Supplementary Fig. S10). ...
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... exposure of macrophages to ox-LDL induced EGFR phosphorylation, but not EGFR expres- sion, as detected by western bott method ( Fig. 4a and Supplementary Fig. S9) and immunofluorescence staining ( Fig. 4b and Supplementary Fig. S10). The levels of p-EGFR were greatly reduced when cells were pre-treatment with 542 or AG1478 ( Fig. 4b and Supplementary Fig. S10). Downstream signaling proteins Akt and ERK were also phosphorylated by ox-LDL and inhibited with 542 and AG1478 ( Fig. 4c and Supplementary Fig. S11a). ...
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... levels of p-EGFR were greatly reduced when cells were pre-treatment with 542 or AG1478 ( Fig. 4b and Supplementary Fig. S10). Downstream signaling proteins Akt and ERK were also phosphorylated by ox-LDL and inhibited with 542 and AG1478 ( Fig. 4c and Supplementary Fig. S11a). As macrophage NF-κ B 18 has been shown to be critical in inflammation, we assessed its activation by western blotting and cell staining. ...
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... macrophage NF-κ B 18 has been shown to be critical in inflammation, we assessed its activation by western blotting and cell staining. Our results show increased NF-κ B p65 subunit in the nuclear protein fraction and increased nuclear staining of macrophages stimulated by ox-LDL, as detected by western bott method ( Fig. 4d and Supplementary Fig. S11b) and immunofluorescence staining ( Fig. 4e and Supplementary Fig. S12). In both assays, 542 and AG1478 markedly inhibited ox-LDL-induced NF-κ B activation. ...
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... macrophage NF-κ B 18 has been shown to be critical in inflammation, we assessed its activation by western blotting and cell staining. Our results show increased NF-κ B p65 subunit in the nuclear protein fraction and increased nuclear staining of macrophages stimulated by ox-LDL, as detected by western bott method ( Fig. 4d and Supplementary Fig. S11b) and immunofluorescence staining ( Fig. 4e and Supplementary Fig. S12). In both assays, 542 and AG1478 markedly inhibited ox-LDL-induced NF-κ B activation. ...
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... of EGFR and downstream signaling proteins by ox-LDL was also associated with induction of pro-inflammatory cytokines TNF-α and IL-6 at both protein and mRNA levels in cultured macrophages. As expected, AG1478 or 542 prevented this induction (Fig. 4f,g, Supplementary Fig. S13a,b). mRNA analysis also showed that AG1478 and 542 suppressed the expression of adhesion molecules ICAM-1 and VCAM-1 induced by ox-LDL (Fig. 4h,i). We then examined MMPs as our studies in aorta tissues showed dysregulated expres- sion and activity in atherosclerotic lesions. In cultured macrophages, ox-LDL increased MMP2 expression and ...
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... cultured macrophages, ox-LDL increased MMP2 expression and MMP9 activity and both of these changes were prevented by AG and 542 pretreatment (Fig. 4j,k). We also tested the anti-inflammatory effects of EGFR inhibitors in cultured SMCs and show responses similar to macrophages ( Supplementary Fig. S14a,b). ...
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... we determined the effects of EGFR inhibitors on ox-LDL-stimulated ROS generation in macrophages. Exposure of macrophages to ox-LDL for 6 h significantly increased ROS gen- eration as indicated by DCFH-DA/DHE fluorescence staining ( Fig. 5a and Supplementary Fig. S15) and flow cytometry (Fig. 5b). Pretreatment with 452 or AG1478 was able to block increased ROS generation. ...
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... with 452 or AG1478 was able to block increased ROS generation. Similar results were obtained in SMCs (Supplementary Fig. S16). To understand how EGFR induces ROS produc- tion following ox-LDL stimulation, we tested the effects of EGFR inhibitors on the expression and activity of NADPH oxidase (NOX) in macrophages. ...
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... has recently been shown to activate infiltrating immune cells, increasing ROS levels in aortic sinus of diabetic mice 23 . Our results showed that both AG1478 and 451 significantly reversed ox-LDL-induced NADP/NADPH ratio and inhibited ox-LDL-induced NOX-1 expres- sion ( Supplementary Fig. S17). In addition, we tested the determination of NO level and iNOS expression in oxLDL-stimulated macrophages. ...
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... addition, we tested the determination of NO level and iNOS expression in oxLDL-stimulated macrophages. It was observed that pre-treatment with EGFR inhibitors significantly blocked oxLDL-induced overproduction of NO and overexpression of iNOS ( Supplementary Fig. S18). ...
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... were incubated with DiI-labled ox-LDL (DiI-ox-LDL) with or without pretreatment with EGFR inhibitors and analyzed by fluorescence microscopy and flow cytometry. Here, we report that inhibition of EGFR prevented ox-LDL update in macrophages (Fig. 5d,e, and Supplementary Fig. S19a). We confirmed these results by staining macrophages exposed to ox-LDL with Oil Red O ( Fig. 5f and Supplementary Fig. S19b). ...
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... we report that inhibition of EGFR prevented ox-LDL update in macrophages (Fig. 5d,e, and Supplementary Fig. S19a). We confirmed these results by staining macrophages exposed to ox-LDL with Oil Red O ( Fig. 5f and Supplementary Fig. S19b). These studies show that EGFR inhibition reduced formation of foam cells. ...
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... and cell culture. AG1478 were purchased from Sigma-Aldrich (St. Louis, MO). Compound 542 (Fig. 1a) was prepared with a purity of 99.2% as described in our previous study 34 . AG1478 and compound 542 were dissolved in dimethyl sulfoxide (DMSO) for in vitro experiments and in 1% sodium carboxyl methyl cellulose (CMC-Na) for in vivo experiments. Antibodies against GAPDH, p-EGFR and p-AKT were purchased from Cell Signaling (Danvers, MA, ...
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Citations
... EGFR deficiency could limit lipid uptake, attenuate the inflammatory response, and impede the development of atherosclerosis. Conversely, the activation of EGFR will lead to the activation of the PI3K/AKT/mTOR signaling pathway, which plays an important role in pathophysiological processes such as hyperlipidemia and atherosclerosis [63]. VEGFA, a member of the VEGF family, plays crucial roles in angiogenesis, regulation of vascular permeability, and maintenance of vascular physiological functions. ...
Hyperlipidemia is a prevalent chronic metabolic disease that severely affects human health. Currently, commonly used clinical therapeutic drugs are prone to drug dependence and toxic side effects. Dietary intervention for treating chronic metabolic diseases has received widespread attention. Rosa sterilis is a characteristic fruit tree in China whose fruits are rich in flavonoids, which have been shown to have a therapeutic effect on hyperlipidemia; however, their exact molecular mechanism of action remains unclear. Therefore, this study aimed to investigate the therapeutic effects of R. sterilis total flavonoid extract (RS) on hyperlipidemia and its possible mechanisms. A hyperlipidemic zebrafish model was established using egg yolk powder and then treated with RS to observe changes in the integral optical density in the tail vessels. Network pharmacology and molecular docking were used to investigate the potential mechanism of action of RS for the treatment of hyperlipidemia. The results showed that RS exhibited favorable hypolipidemic effects on zebrafish in the concentration range of 3.0–30.0 μg/mL in a dose-dependent manner. Topological and molecular docking analyses identified HSP90AA1, PPARA, and MMP9 as key targets for hypolipidemic effects, which were exerted mainly through lipolytic regulation of adipocytes and lipids; pathway analysis revealed enrichment in atherosclerosis, chemical carcinogenic-receptor activation pathways in cancers, and proteoglycans in prostate cancer and other cancers. Mover, chinensinaphthol possessed higher content and better target binding ability, which suggested that chinensinaphthol might be an important component of RS with hypolipidemic active function. These findings provide a direction for further research on RS interventions for the treatment of hyperlipidemia.
... EGFR has been associated not only with vascular homeostasis but also with diverse pathologies, including cardiovascular diseases such as hypertension or atherosclerosis 31,32 , in which it appears mostly harmful. We previously described a role of EGFR in EC for the regulation of basal vascular function in vivo, using a transgenic mouse model. ...
Endothelial cells (EC) are key players in vascular function, homeostasis and inflammation. EC show substantial heterogeneity due to inter-individual variability (e.g. sex-differences) and intra-individual differences as they originate from different organs or vessels. This variability may lead to different responsiveness to external stimuli. Here we compared the responsiveness of female human primary EC from the aorta (HAoEC) and coronary arteries (HCAEC) to Epidermal Growth Factor Receptor (EGFR) activation. EGFR is an important signal integration hub for vascular active substances with physiological and pathophysiological relevance. Our transcriptomic analysis suggested that EGFR activation differentially affects the inflammatory profiles of HAoEC and HCAEC, particularly by inducing a HCAEC-driven leukocyte attraction but a downregulation of adhesion molecule and chemoattractant expression in HAoEC. Experimental assessments of selected inflammation markers were performed to validate these predictions and the results confirmed a dual role of EGFR in these cells: its activation initiated an anti-inflammatory response in HAoEC but a pro-inflammatory one in HCAEC. Our study highlights that, although they are both arterial EC, female HAoEC and HCAEC are distinguishable with regard to the role of EGFR and its involvement in inflammation regulation, what may be relevant for vascular maintenance but also the pathogenesis of endothelial dysfunction.
... Vascular EGFR has been associated with cardiovascular health and diseases thanks to knock-out animal studies and targeted approaches in cell culture. [3][4][5][6]13 But to our knowledge, our untargeted study is the first one that reports the global effect of EGFR activation on the transcriptome of primary human VSMC. Our analysis suggests that EGFR activation in these cells primarily leads to a phenotypical switch from a differentiated/contractile to a de-differentiated/proliferative state. ...
... The proteins coded by these particular EGF-regulated genes have been described as regulators of cardiovascular pathologies, 19,25,26 and more generally, enhanced inflammatory states by VSMC have been observed at vascular injury sites and associated with the setting up of vascular diseases such as atherosclerosis. 27 An EGFR-related inflammatory state in VSMC have actually been previously reported by Wang et al., 13 who showed that EGFR inhibition led to a reduced expression of inflammation markers by human VSMC. However, they appear to have used cells from a single donor (unspecified sex and unknown EGFR expression level). ...
Vascular smooth muscle cells (VSMC) are critical for the vascular tone, but they can also drive the development of vascular diseases when they lose their contractile phenotype and de-differentiate. Previous studies showed that the epidermal growth factor receptor (EGFR) of VSMC is critical for vascular health, but most of the underlying mechanisms by which VSMC-EGFR controls vascular fate have remained unknown. We combined RNA-sequencing and bioinformatics analysis to characterize the effect of EGFR-activation on the transcriptome of human primary VSMC (from different female donors) and to identify potentially affected cellular processes. Our results indicate that the activation of human VSMC-EGFR is sufficient to trigger a phenotypical switch toward a proliferative and inflammatory phenotype. The extent of this effect is nonetheless partly donor-dependent. Our hypothesis-generating study thus provides a first insight into mechanisms that could partly explain variable susceptibilities to vascular diseases in between individuals.
... [61][62][63] EGFR plays a role in foam cell transformation, and cellular dysfunction and proliferation of VSMCs. [64] Lintao Wang et al found that the inhibition of EGFR could decrease inflammation and oxidative stress to attenuate AS. [65] Intracellular MAPK signaling cascade is considered to play an important role in the pathogenesis of cardiovascular disease. [66] MAPKs regulates the formation of atherosclerotic lesions by regulating the transformation of macrophages into foam cells. ...
Background
Guanxinning tablet (GXNT), a Chinese patent medicine, is composed of salvia miltiorrhiza bunge and ligusticum striatum DC, which may play the role of endothelial protection through many pathways. We aimed to explore the molecular mechanisms of GXNT against atherosclerosis (AS) through network pharmacology and molecular docking verification.
Methods
The active ingredients and their potential targets of GXNT were obtained in traditional Chinese medicine systems pharmacology database and analysis platform and bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine databases. DrugBank, TTD, DisGeNET, OMIM, and GeneCards databases were used to screen the targets of AS. The intersection targets gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were performed in DAVID database. GXNT-AS protein-protein interaction network, ingredient-target network and herb-target-pathway network were constructed by Cytoscape. Finally, we used AutoDock for molecular docking.
Results
We screened 65 active ingredients of GXNT and 70 GXNT-AS intersection targets. The key targets of protein-protein interaction network were AKT1, JUN, STAT3, TNF, TP53, IL6, EGFR, MAPK14, RELA, and CASP3. The Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling pathway were the main pathways. The ingredient-target network showed that the key ingredients were luteolin, tanshinone IIA, myricanone, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone. The results of molecular docking showed that tanshinone IIA, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone all had good binding interactions with AKT1, EGFR and MAPK14.
Conclusion
The results of network pharmacology and molecular docking showed that the multiple ingredients within GXNT may confer protective effects on the vascular endothelium against AS through multitarget and multichannel mechanisms. AKT1, EGFR and MAPK14 were the core potential targets of GXNT against AS.
... Knock-out animals showed significantly reduced angiotensin II-induced renal inflammation, indicated by lower IL6 and MCP1 expression [156]. Evidence for a systemic pathophysiological relevance was proved by a study showing that EGFR inhibitors decrease inflammation markers (TNFα, IL6) in atherosclerotic plaques of mice and their macrophages, as well as in in human VSMC [157]. ...
... In the previous section, we reported that a high number of animals in the SMMHC EGFR KO group died during the procedure, and the data needed to be excluded from further analysis. Unfortunately, we did not investigate the cause of death further, but it was recognized that, in some animals, blood could be found in the big body cavities; it needs to be elucidated in further studies whether this finding was a result of altered atherosclerotic lesion formation [20]. ...
(1) Background: Obesity is associated with hypertension because of endocrine dysregulation of the adrenergic and the renin–angiotensin–aldosterone systems. The epidermal growth factor receptor (EGFR) is an important signaling hub in the cardiovascular system. In this study, we investigate the role of smooth muscle cell (VSMC) and endothelial cell (EC) EGFRs for blood pressure homeostasis and acute vascular reactivity in vivo. (2) Methods: Mice with deletion of the EGFR in the respective cell type received either a high-fat (HFD) or standard-fat diet (SFD) for 18 weeks. Intravascular blood pressure was measured via a Millar catheter in anesthetized animals upon vehicle load, angiotensin II (AII) and phenylephrine (PE) stimulation. (3) Results: We confirmed that deletion of the EGFR in VSMCs leads to reduced blood pressure and a most probably compensatory heart rate increase. EC-EGFR and VSMC-EGFR had only a minor impact on volume-load-induced blood pressure changes in lean as well as in obese wild-type animals. Regarding vasoactive substances, EC-EGFR seems to have no importance for angiotensin II action and counteracting HFD-induced prolonged blood pressure increase upon PE stimulation. VSMC-EGFR supports the blood pressure response to adrenergic and angiotensin II stimulation in lean animals. The responsiveness to AII and alpha-adrenergic stimulation was similar in lean and obese animals despite the known enhanced activity of the RAAS and the sympathetic nervous system under a high-fat diet. (4) Conclusions: We demonstrate that EGFRs in VSMCs and to a lesser extent in ECs modulate short-term vascular reactivity to AII, catecholamines and volume load in lean and obese animals.
... While the expression and function of the epidermal growth factor receptor (EGFR)/ERBB1 has been extensively studied in normal and malignant cells of epithelial and mesenchymal origins, very little is understood regarding its expression in normal or malignant lymphoid cells. However, recent studies indicated that lymphoid cells also express ERBB1 [16][17][18][19][20]. Notably, ERBB1 ligands AREG and EGF have been shown to stimulate the proliferation of multiple myeloma (MM) cells [21,22], and inhibiting ERBB1 caused cytotoxicity to MM cells [23,24]. ...
The main goal of the present study was to examine if the RNA-sequencing (RNAseq)-based ERBB2/HER2 expression level in malignant plasma cells from multiple myeloma (MM) patients has clinical significance for treatment outcomes and survival. We examined the relationship between the RNAseq-based ERBB2 messenger ribonucleic acid (mRNA) levels in malignant plasma cells and survival outcomes in 787 MM patients treated on contemporary standard regimens. ERBB2 was expressed at significantly higher levels than ERBB1 as well as ERBB3 across all three stages of the disease. Upregulated expression of ERBB2 mRNA in MM cells was correlated with amplified expression of mRNAs for transcription factors (TF) that recognize the ERBB2 gene promoter sites. Patients with higher levels of ERBB2 mRNA in their malignant plasma cells experienced significantly increased cancer mortality, shorter progression-free survival, and worse overall survival than other patients. The adverse impact of high ERBB2 expression on patient survival outcomes remained significant in multivariate Cox proportional hazards models that accounted for the effects of other prognostic factors. To the best of our knowledge, this is the first demonstration of an adverse prognostic impact of high-level ERBB2 expression in MM patients. Our results encourage further evaluation of the prognostic significance of high-level ERBB2 mRNA expression and the clinical potential of ERBB2-targeting therapeutics as personalized medicines to overcome cancer drug resistance in high-risk as well as relapsed/refractory MM.
... Growth factor receptors (EGFR) can accelerate the formation of atherosclerotic lesions (85). It has been reported that METTL3 is decreased in atherosclerosis regions. ...
Cardiovascular diseases (CVDs) have been established as a major cause of mortality globally. However, the exact pathogenesis remains obscure. N6-methyladenosine (m⁶A) methylation is the most common epigenetic modification on mRNAs regulated by methyltransferase complexes (writers), demethylase transferases (erasers) and binding proteins (readers). It is now understood that m⁶A is a major player in physiological and pathological cardiac processes. m⁶A methylation are potentially involved in many mechanisms, for instance, regulation of calcium homeostasis, endothelial function, different forms of cell death, autophagy, endoplasmic reticulum stress, macrophage response and inflammation. In this review, we will summarize the molecular functions of m⁶A enzymes. We mainly focus on m⁶A-associated mechanisms and functions in CVDs, especially in heart failure and ischemia heart disease. We will also discuss the potential application and clinical transformation of m⁶A modification.
... Intriguingly, Zaiss et al. reported that CD4 + T-cells express ERBB1 in an antigen-dependent manner [13], which enables them to mount an innate-like immune response during gastrointestinal helminth infections [14]. ERBB1 signaling pathways play key roles in regulating T-cell homeostasis [15], and they may also influence the pathophysiology of atherosclerosis as a T-cell-mediated inflammatory disease [16]. ERBB1 expression was detected in a B-ALL cell line and shown to promote stroma-independent survival and growth [17]. ...
We examined the transcript-level expression of ErbB family protein tyrosine kinases, including ERBB1, in primary malignant lymphoma cells from 498 adult patients with diffuse large B-cell lymphoma (DLBCL). ERBB1 expression in DLBCL cells was significantly higher than in normal B-lineage lymphoid cells. An upregulated expression of ERBB1 mRNA in DLBCL cells was correlated with an amplified expression of mRNAs for transcription factors that recognized ERBB1 gene promoter sites. Notably, amplified ERBB1 expression in DLBCL and its subtypes were associated with significantly worse overall survival (OS). Our results encourage the further evaluation of the prognostic significance of high-level ERBB1 mRNA expression and the clinical potential of ERBB1-targeting therapeutics as personalized medicines in high-risk DLBCL.
... These components also impact endothelial function, oxidative stress, inflammation, cellular activity, and plaque stability [48]. Conversely, the inhibition of the epidermal growth factor receptor (EGFR) has been demonstrated to be effective in preventing the formation of atherosclerotic lesions, reducing inflammation, and suppressing the generation of reactive oxygen species and foam cell formation [49]. In vitro studies have also indicated that prolactin plays a role in the development of endothelial dysfunction in atherosclerosis through its ability to modulate the inflammatory response, stimulate vascular smooth muscle cell proliferation, and regulate mononuclear cell adhesion to the endothelium [50]. ...
Atherosclerosis, a pathological condition marked by the accumulation of lipids and fibrous substances in the arterial walls, is a leading cause of heart failure and death. The present study aimed to utilize network pharmacology to assess the potential pharmacological effects of bioactive compounds in Tualang honey on atherosclerosis. This is significant as previous studies have indicated the cardioprotective effects of Tualang honey, yet a comprehensive evaluation using network pharmacology has yet to be conducted. The bioactive compounds in Tualang honey were screened and the potential gene targets for these compounds were predicted through Swiss Target Prediction and SuperPred databases. Atherosclerosis genes were retrieved from the OMIM, DisGeNet, and GeneCards databases. The interaction between these compounds and atherosclerosis genes was established through protein–protein interaction, gene ontology, and KEGG pathway analysis. The results of these analyses were then further confirmed through molecular docking studies using the AutoDock Tools software. The results revealed that 6 out of 103 compounds in Tualang honey met the screening criteria, with a total of 336 potential gene targets, 238 of which were shared with atherosclerosis. Further analysis showed that these active compounds had a good affinity with key targets and were associated with biological processes related to protein phosphorylation and inflammation as well as pathways related to lipid and atherosclerosis and other signaling pathways. In conclusion, the study provides insight into the potential pharmacological effects of Tualang honey bioactive compounds on atherosclerosis, supporting its use as a promising treatment for the disease.
