To conduct a bibliometric analysis of recent genetic studies related to arterial hypertension (AH), we searched the PubMed online database on 25 April 2023. The search strategy used was: “Search: {[arterial hypertens*(Title/Abstract)] OR [arterial hypertens*(MeSH Terms)]} AND {[gene (MeSH Terms)] OR [gene (Title/Abstract)]} Filters: from 2018–2023”. We used VOSviewer software to perform the bibliometric analysis and identify the most frequent genetic-related MeSH keywords (Van Eck and Waltman, 2010). We excluded some general MeSH keywords from their analysis, including human, male, female, hypertension, blood pressure, familial primary pulmonary hypertension, all Mesh keywords that belong to animals, all Mesh keywords that belong to age, cell, cultured, endothelial cells, muscle and smooth muscle, lung, hypoxia and biomarkers. We also performed an Overlay visualization using VOSviewer to determine the time range in which the most frequent genetic-related MeSH keywords were studied.

The use of bibliometric analysis has become increasingly popular in biomedical research for identifying research trends, and hot topics. In previous studies, bibliometric analysis has been used to investigate the global trends and research focus of hypertension, identifying key research areas and influential authors (Donthu et al., 2021). In addition, network visualization analysis has been used to visualize the co-citation of hypertension-related genes and pathways. By using these methods, researchers have been able to identify potential therapeutic targets and biomarkers for hypertension.

We conducted a deep search in Google Scholar on 26 April 2023, to identify microRNAs and genes involved in AH. They used the following search strategies: 1) allintitle: hypertension microRNA “arterial hypertension” -review–overview, and 2) allintitle: hypertension “gene” “arterial hypertension” -review -overview.

We obtained the structure of microRNAs and genes from mirBASE (Kozomara and Griffiths-Jones, 2014) and the National Center for Biotechnology Information (NCBI) (Sayers et al., 2021), respectively. They then performed a docking analysis of microRNAs and target genes using RNAhybrid (Rehmsmeier et al., 2004).

Molecular docking is a computational method that has been used to predict the binding affinity of small molecules to target proteins (Fan et al., 2019). In recent years, molecular docking has been applied to predict the binding of microRNAs to their target genes (Zhou et al., 2022). This approach has been used to identify potential miRNA-gene interactions involved in the pathogenesis of hypertension. By using RNAhybrid for docking analysis of microRNAs and target genes, we can identify potential regulatory mechanisms of the genes involved in AH.

Cytoscape software (Shannon et al., 2003) was utilized in order to visualize Network between microRNAs and genes. Network visualization has been used to visualize complex interactions between genes, microRNAs, and other biomolecules. In previous studies, network visualization has been used to identify key pathways and molecular interactions involved in the pathogenesis of hypertension. By using Cytoscape for network visualization, we can identify potential regulatory networks of microRNAs and genes involved in AH, potentially identifying new therapeutic targets and diagnostic biomarkers.

Based on our network analysis, we identified 1,138 related articles on the genetic factors associated with arterial hypertension. Using VOSviewer software, we further divided these articles into 971 items, 19 clusters, 18,828 links, and a total link strength of 25,131. Our analysis revealed that the most frequent MeSH keywords related to genetic factors in arterial hypertension were genetic predisposition to disease, microRNA, gene expression regulation, and single nucleotide polymorphism (SNP), as shown in Table 1 and Figure 2. These keywords have been extensively studied in previous research on the genetic basis of arterial hypertension, suggesting their importance in understanding the underlying mechanisms of this disease.

Besides, overlay visualization confirms that all the mentioned MeSH keywords have been examined 155 in related field since 2018 (Figure 3).

Various genes and their polymorphism and their different roles in AH are collected in Table 2. Table 2 provides information on genes, their polymorphisms, and alleles that play a role in arterial hypertension in various populations. The table lists the gene name, gene polymorphism, genotype, allele, the effect of the gene on arterial hypertension, ethnicity/territory, and reference. The table indicates that various genes such as 11β-HSD1, 5-HTT, 5-HTTLPR, ACE, ADD1, AGT, AGTR1, APOE, COX-2, DRD2, EDN1, ERBB3, HIF1α, IRS1, ITGA2, MMP-9, MTHFR, NOS2, RASA3, RNF213, SCNN1A, TBX2, TNF, TNFR2, and VDR have been identified to be associated with arterial hypertension in different populations. For each gene, the table provides details on the specific polymorphism and allele, along with the ethnicity/territory where the association was found and the reference for the study.

Table 3 summarizes the epigenetic mechanisms that play a role in the development or worsening of arterial hypertension. It includes the gene name, the affecting mechanism(s) on the gene, and the result of the affecting mechanism(s) on the gene, along with the corresponding reference. The table shows that hyper methylation of the CBS promoter gene increases the risk of hypertension and stroke. Hyper-methylation of BMPR2 increases the risk of pulmonary arterial hypertension (PAH), while acetylation of H3K27 also increases the risk of PAH. Additionally, hypo methylation of SOCS3 promoter increases the risk of PAH. Other epigenetic factors and their functions in AH are displayed in Table 3.

Table 4 contains different types of microRNAs that involve in AH and also their mechanism in mentioned disease. Table 4 presents various microRNAs that have been studied in the context of arterial hypertension (AH) from 2018 to 2023. These microRNAs have different roles in AH and their mechanisms are also mentioned in the table. miR-140-5p suppresses the proliferation, migration, and phenotypic variation of PASMCs. miR-204 suppresses Tgfbr2 while miR‐206 downregulates Kv1.5. miR-328-3p suppresses cell viability, migration, and the levels of VEGF, FGF-2 and HIF-1α in hypoxia-induced PASMCs. Other microRNAs have either amelioration or amplification roles in AH with different mechanisms of action. ND refers to “not determined”. The references for the studies are also mentioned in the table.

After obtaining the structure of collectedd microRNAs from mirBASE (Kozomara and Griffiths-Jones, 2014) and also achieving the structure of target genes from the National Center for Biotechnology Information (NCBI) (Sayers et al., 2021), docking analysis of microRNAs and target genes was conducted by using RNAhybrid (Rehmsmeier et al., 2004).

Table 5 has the detailed information about binding affinity of various microRNA and genes that play a part in AH. According to remarked table, MicroRNA-7110-5p has the most binding affinity to 11 beta hydroxysteroid dehydrogenase type 1 (11β-HSD1), serotonin transporter (5-HTT), and D2-dopaminergic receptor (DRD2). Moreover, MiR-7110-3p has the most binding affinity to integrin subunit alpha 2I (ITGA2) and MicroRNA-663. Besides, MicroRNA-663 demonstrated the most binding affinity to Angiotensinogen II Type 1 Receptor (AGTR1), Angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR), Apo lipoprotein E (APOE), Angiotensinogen II Type 1 Receptor (AGTR1), Angiotensin-converting enzyme (ACE), methylenetetrahydrofolate reductase (MTHFR), endothelin1 (EDN1) ring finger protein 213 (RNF213), Alpha-Adducin 1 (ADD1), and tumor necrosis factor (TNF). Furthermore, MiR-328-3p has the most binding affinity to vitamin D receptor (VDR), sodium channel epithelial 1 subunit alpha (SCNN1A) and angiotensinogen (AGT), and ultimately, MiR-140-5p has the most binding affinity to Hypoxia-inducible factor 1α (HIF1α). Besides, Figure 4 demonstrated the nucleotides that involve in the binding site of all mentioned microRNAs and genes.

Previous studies have confirmed the role of various genes and their polymorphism and also their single nucleotide in the pathophysiology of AH (Shnayder et al., 2021). Our study demonstrated that Genetic predisposition to disease and Polymorphism, single nucleotide are two factors that have been most frequent MeSH key words in related studies from 2018 to 2023 (Table 1; Figure 2). This finding is confirmed by prior surveys in which the role of genetic factors has been examined. Besides, previous surveys have mentioned that scientists have been trying to discover various genetic factors and pathways that involve in pathophysiology of AH (Friso et al., 2015).

One of the most interesting keywords in the field of the genetic factors and their role in AH is gene expression regulation (Table 1). On the other side, one important way in order to regulate gene expression is using epigenetic factors for regulating gene expression. In better words, epigenetic factors, have gained the attention of scientists for examining their role in AH (Friso et al., 2015). Epigenetic factors are defined as heritable traits that alter the expression of human genes without making any change in the structure of DNA sequence. They have involved in the pathogenesis of many cardiovascular diseases including PAH. In other words, epigenetic factors in accompanying with genetic mechanisms play a crucial role in the dysregulation of network-based molecular architecture in cellular level in AH (Napoli et al., 2019). DNA methylation, histone modifications, mRNA methylation, and noncoding RNA modifications are major types of epigenetic factors (Barroso et al., 2014). These epigenetic mechanisms with genetic factors and environmental risk factors play a crucial role in occurrence and intensity of both vascular endothelial cells as well as AH (Napoli et al., 2019). Besides, based on previous researches, there are five available curative strategies in order to treat AH including endothelin receptor antagonists, prostanoid analogues, phosphodiesterase type 5 inhibitors, nonprostanoid IP receptor agonists, and soluble guanylyl cyclase stimulators. Albeit the benefits of all mentioned curative strategies, some serious side effects still exists (Jain et al., 2017). Hence, scientists have tried to develop more effective therapeutic agents. One of these curative agents are epigenetic drugs (epidrugs) which have gained the attention of researchers in recent years (Napoli et al., 2016). For example, SIN3a (switch-independent 3a), a transcriptional regulator has been utilized to regulate methylation and expression levels of the bone morphogenetic protein receptor type 2 (BMPR2) gene in human pulmonary arterial smooth muscle cells. SIN3a suppresses the methylation of BMPR2 and increased the expression of it. Thus, SIN3a can protect these cells against pathological changes that end to AH (Bisserier et al., 2021). Furthermore, previous studies demonstrated that hyper methylation of BMPR2 can oppress the proliferation of vascular cells which is crucial for developing and intensifying PAH. This finding make BMPR2 a proper candidate for being an effective epidrug and also a target for anti-AH therapeutic agents in near future (Napoli et al., 2019). In fact, SIN3a exerted its action by downregulating the expression of DNMT1 (DNA methyltransferase 1) and EZH2 (enhancer of zeste 2 polycomb repressive complex 2) and up-regulating the expression of the TET1 (ten-eleven translocation methylcytosine dioxygenase 1) (Bisserier et al., 2021). The other fascinating epigenetic factor that seems to be a potential future epidrug is hyper methylated ABCA1 (ATPbinding cassette 1). This microRNA blocks vascular cells in mitotic phase and prevent AH to become progressive (Napoli et al., 2019).

Notably, oxidative stress underlying PAH phenotype is formed by cooperation between hyper acetylation of cyclophilin a (CypA) with downregulation of antioxidant superoxide dismutase 3 (SOD3) (Napoli et al., 2019). On the other side, scientists have found out that some epigenetic modifications can worsen AH. For instance, the acetylation of H3K27ac (histone H3 lysine 27) by acetyl coenzyme A can create proper condition for the acetyltransferase KAT2B (lysine acetyltransferase 2B) and activation of genes that involve in cell cycle and metabolic events, that is, required for aldehyde dehydrogenase family 1 member 3 (ALDH1A3) - dependent proliferation and glycolysis. Finally, this activation leads to amplification of AH (Li D. et al., 2021) which we have displayed in Table 3.

Moreover, acetylation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) causes sustaining the vascular proliferation in the condition of PAH through downregulation of SIRT1 HDAC (histone deacetylase) (Napoli et al., 2019).

Besides, scientists have found that there is a connection between pulmonary arterial hypertension (PAH) in rat model and hyper methylation of RASEF. In this survey, the exposure of rats to smoking caused increase the level of hyper methylation in RASEF and occurrence of some changes including right ventricular hypertrophy, increasing the thickness right ventricular, and raising systolic blood pressure was observed. Notably, remarked research have conveyed that overespression of RASEF can inhibit AH through downregulation of phospho-AKT (Ser473), proliferating cell nuclear antigen (PCNA), and matrix metalloproteinase 9 (MMP9). Thereby, it is plausible that hyper methylation of RASEF exerts its role through upregulation of mentioned factors. Ultimately, this study endorsed the companionship between hyper methylation of RASEF and PAH (Li et al., 2019).

In brief, according to Table 3, DNA hyper methylation, hyper acetylation and DNA acetylation have been introduced as epigenetic factors in order to regulate gene expression in AH since 2018. As you can see in remarked table, epigenetic factors have a variety of effects in the process of pathology of AH. Interestingly, prior researches have demonstrated that post-translational modifications including hyper methylation and acetylation are known as a crucial factor for developing AH and also have diverse impacts on mentioned pathological condition (Friso et al., 2015). Thus, the results from our bibliometric analysis are confirmed by previous surveys.

MicroRNAs (miRNAs) are small non-coding RNA molecules that previous surveys have proved that they are expressed in AH and they can play a crucial part in the pathogenesis of AH (Synetos et al., 2013). These kinds of RNAs involve in various mechanisms that ends to effect on AH including participating in the functions of arterial endothelial cells which contain receiving mechanical stimuli and transform them into intracellular signals, inducing alteration of cellular structure and function. The other role of microRNAs in the pathophysiology of AH is playing a remarkable role in regulation of leucocyte adhesion on the surface of endothelial cells, inflammatory processes, vasodilatory activities, and proliferation of endothelium. Besides, microRNAs can effect Nitric oxide (NO) dependent vasodilatation through adjusting the level of NO in human body, since upregulation of NO can lead to increase in blood pressure. The other impact of microRNA is involving in the regulation of the activity of vascular smooth muscle cells (VSMCs) (Klimczak et al., 2017). VSMCs have the capability for adapting their phenotype based on current condition. In other words, when these cells were undergone vascular damage caused by high blood pressure, they turn from contractile cells to synthetic ones (Owens et al., 2004). Subsequently, they start to raise proliferation, migration, collagen and extracellular matrix synthesis, as well as deduct expression of contractility markers (Kawai-Kowase and Owens, 2007). Interestingly, microRNAs have the capability to adjust phenotype of VMSCs in the situations in which vascular damages are occurred by AH (Klimczak et al., 2017). As we mentioned in Table 4, some microRNAs including miR-15a-5p, miR-30a, miR-30d-5p, miR-328-3p, and miR-663 are responsible for making VSMCs to form proper phenotype during damaging process of AH. Furthermore, microRNAs contribute to the process of AH by interfering in the functions of sympathetic nervous system and renin–angiotensin system (RAS) (Klimczak et al., 2017). Although the studies about the roles of microRNAs in the sympathetic nervous system have been limited but some surveys have demonstrated these RNAs can link sympathetic nervous system with RAS and also have the ability to regulate renin mRNA (Jackson et al., 2013). On the other side, RAS which plays a vital role in the pathogenesis of AH, has the capability to effect various organs both directly and indirectly can modulate by 55 microRNA species through activation of angiotensin II type 1 receptor (AT1R) (Velloso et al., 1996; Kemp et al., 2014). Ultimately, another function of microRNAs in the process of pathogenesis of AH in inhibiting inflammation by downregulation of IL6 (Wang et al., 2013). Figure 5 displays a whole paradigm of the various roles of microRNAs in the pathology of AH. Interestingly, our Network visualization displayed that a major number of early studies in the field of examining the genetic functions in AH have focused on miRNAs. Besides, some prior surveys have tried to utilize in silico studies in order to discover the role of miRNAs and their probable target genes that play a crucial role in AH. For example, in early studies, the role of circulating Let-7b on pulmonary hypertension was examined and its target genes were determined through in silico analysis (Guo et al., 2014). Moreover, other in silico surveys have demonstrated the effects of some gene polymorphisms that play a part in AH on the function of some miRNAs (Ya et al., 2015). Our study demonstrated that miRNAs can be an important element in the process of pathophysiology of AH. This is in line with other previous similar studies. On the other side, Table 4 demonstrates various classes of miRNAs and their detailed role in AH. As it is displayed in this table, miRNAs have various effects in AH. This result in line with the findings of prior surveys (Synetos et al., 2013).

According to our bibliometric analysis, all of the most frequent MeSH keywords in related field that are listed in Table 1 have been undergone various studies since 2019 (Figure 3). Besides, all of them have gained the attention of scientists that have vast activities in the field of AH. Thus, the result of overlay visualization in present survey confirms that scientists have been trying to elucidate the role of various genetic factors in the pathophysiology of AH (Figure 3).

MicroRNAs have an important role in the process of AH. these molecules have gained the attention of scientists who works on AH (Table 1 and Figure 2). Despite this, the exact and detailed mechanisms of these molecules in pathophysiology of AH is still unclear and needs various in-vitro and in-vivo examinations (Johnson et al., 2020). Hence, in this study, we tried to elucidate a part of the role of recent discovered microRNAs that have shown remarkable impacts in the pathophysiology of AH in in silico condition (Table 5). Moreover, we demonstrated the possible network of the role of microRNAs with the most affinity to discovered genes that play a part in AH in Figure 6. Although the findings of present study may guide researchers to pay more attention to mentioned microRNAs and genes but more surveys need to be conducted in the future for revealing the detailed mechanisms of action of microRNAs in AH.