Research hotspots and trends regarding microRNAs in hypertension: a bibliometric analysis

ABSTRACT

To investigate the research levels, hotspots, and development trends regarding microRNAs in hypertension, this study conducted a visual analysis of studies on miRNA in hypertension based on the Web of Science core collection database using CiteSpace and VOSviewer analysis software along with literature from 2005–2023 as information data. Using citation frequency, centrality, and starting year as metrics, this study analyzed the research objects. It revealed the main research bodies and hotspots and evaluated the sources of literature and the distribution of knowledge from journals and authors. Finally, the potential research directions for miRNAs in hypertension are discussed. The results showed that the research field is in a period of vigorous development, and scholars worldwide have shown strong interest in this research field. A comprehensive summary and analysis of the current research status and application trends will prove beneficial for the advancement of this field.

KEYWORDS:

• Bibliometric analysis
• MicroRNA
• hypertension
• VOSviewer
• CiteSpace

Introduction

The pathogenesis of hypertension is debatable, because it is a complex polygenic chronic hereditary disease caused by alternating environmental and genetic factors.^1,2 Exploring the pathogenesis of hypertension and identifying therapeutic targets remains the focus of current research in the pharmaceutical industry. It has been reported that microRNAs (miRNAs) play an important role in the development of hypertension through specifically recognizing complementary sequences in the 3”-end untranslated region (3”−UTR) of target mRNAs, causing degradation or translational inhibition of the target mRNAs, and extensively regulating the biological processes of cell proliferation, differentiation, senescence, and apoptosis at the post-transcriptional level.³ To date, thousands of studies have been published on miRNA research in hypertension. Several reports have indicated abnormal expression of miR-155 in preeclampsia (PE) and its association with severe clinical manifestations. This was validated through establishing a placental-specific miR-155 overexpression mouse model, which confirmed its pivotal role in the occurrence and progression of PE. Furthermore, the roles and mechanisms of the miR-29 family in cardiac development and cardiac-related diseases were explored. The miR-29 family may emerge as novel diagnostic markers and therapeutic targets for cardiovascular diseases.^4,5 However, there are several limitations to the current research on miRNAs in hypertension, one of which is the lack of a comprehensive summary and analysis of the present research status and application trends. Most existing studies are based on traditional literature reviews, which are constrained by subjective selection, qualitative descriptions, and a lack of visualization. Therefore, it is essential to employ a more objective and quantitative approach to uncover the research progress, hot topics, and future directions in this field. Quantitative analysis is a scientific method that utilizes mathematical and statistical techniques to measure and evaluate the quantity, quality, structure, and impact of scientific literature in a specific domain or subject. It can aid researchers in understanding the evolving trends, knowledge structures, collaboration networks, and knowledge dissemination within a research field over time.^6,7 In this study, we conducted a quantitative analysis of the literature on miRNAs in hypertension from 2005 to 2023 using CiteSpace and VOSviewer software, based on the Web of Science (WOS) Core Collection database. Our aim was to provide a reference for understanding the current research status, cutting-edge trends, and future developments in this field.

Materials and methods

Data source

The WOS core collection was used as the database with the following query: TS = ((“Hypertension” OR “Blood Pressure, High” OR “Blood Pressures, High” OR “High Blood Pressure” OR “High Blood Pressures”) NOT (“Pulmonary Hypertension”) AND (“MicroRNAs” OR “MicroRNAs” OR “MicroRNAs” OR “miRNAs” OR “OR ‘Micro RNA’ OR ‘RNA, Micro’ OR ‘miRNA’ OR ‘PrimaryMicroRNA’ OR ‘MicroRNA, Primary’ OR ‘Pri-miRNA’ OR ‘PrimiRORNA’ OR ‘RNA, Temporal Small’ OR ‘Temporal RNA, Temporal RNA, Temporal RNA, Temporal RNA, Primary’ OR ‘Temporal RNA, Temporal RNA, Temporal RNA, Temporal RNA, Primary’ OR Small” OR “stRNA” OR “Small Temporal RNA” OR “pre-miRNA” OR “pre miRNA”)). The search period was from January 1, 2005, to January 1, 2023, the literature types were “Article” and “Review,” and the language was restricted to English. A total of 1494 valid papers were identified after screening. The literature search and screening processes are shown in Figure 1.

Figure 1. Flow chart of bibliometric analysis.

Study method

Bibliometric assessments can provide objective data on scientific outputs, such as basic or clinical areas of medicine, thereby helping researchers understand the development of the field over time.^8–11 VOSviewer, developed by Eck and Waltman (Center for Science and Technology Studies, Leiden, Netherlands), is a visualization and bibliometric software for mapping knowledge and is suitable for processing large-scale data, constructing relationship networks, and visualizing data analysis.¹² CiteSpace was developed by Professor Chaomei Chen at Drexel University in the United States to visually analyze and present scientific literature in a specific field.¹³ CiteSpace software (version 6.1. R6) and VOSviewer (version 1.6.1 9) were employed in this study for bibliometric analysis and visualization, using the VOSviewer software, a country distribution analysis and institutional collaboration network analysis were performed on the literature to show the output, influence and cooperation of different countries and institutions in the field. Origin 2021 was used for the data management and annual publication analyses.

Results

Publication characteristics analysis

The number of publications directly reflects changes in the amount of knowledge.¹⁴ Based on the publication year, the annual number of publications served as the total annual publication volume. As shown in Figure 2a, the literature on miRNAs in hypertension from January 1, 2005, to January 1, 2023, comprised 1494 papers. The total annual publication volume showed an increasing trend, with some fluctuations. The research progress can be divided into three stages: (1) From 2005 to 2012, it was the initial stage, and the number of publications was relatively small, with less than 50 papers per year. During this period, the high-throughput sequencing technology was still in its early stage of development, and there was little understanding of the related hypertension research; (2) From 2013 to 2017, it was a steady development stage, and the number of relevant publications increased year by year, reaching 151 in 2017. This could be attributed to the steady advancement of high-throughput sequencing technology during this period, with gradual improvements in the technology; the prevalence of hypertension was as high as 45.4%, which gradually drew attention to this research field.¹⁵; (3) from 2018 to January 1, 2023, research on miRNAs in hypertension entered a rapid development stage, although it decreased after peaking in 2020, which may be related to the social context, economic conditions, and medical level at that time. In addition, in terms of document types, there were 1154 articles, accounting for approximately 77% (Figure 2b), indicating that more attention has been paid to clinical practice in this field, and original research is mainstream in the field of miRNA research on hypertension. The results of the current study revealed that research on microRNAs in the field of hypertension predominantly focuses on several key areas, including circulating microRNAs, SNP-driven microRNA profiles, miRNA-regulated target genes, the relationship between microRNAs and hypertension-related diseases, and microRNA-mediated signaling pathways. These areas collectively underscore the significant role of miRNAs in the development and occurrence of hypertension as well as their potential as biomarkers and therapeutic targets for the diagnosis and treatment of hypertension. Supporting the experimental research literature further reinforces the findings of this study. Differential expression of circulating miRNAs in hypertensive patients compared to that in normal individuals is evident in some studies. Significantly associated miRNAs, such as miR-126-3p, miR-182-5p, and miR-30a-5p, have been identified in known hypertension, suggesting their potential utility as diagnostic biomarkers or therapeutic targets.¹⁶ Additionally, using the Dahl salt-sensitive rat model, 68 circulating miRNAs capable of distinguishing between hypertensive emergencies and complications were identified. Network analysis revealed the involvement of these miRNAs in critical signaling pathways, such as oxidative stress, apoptosis, and inflammatory responses.¹⁷ These research findings collectively highlight circulating miRNAs as a focal point in the field of hypertension, aligning with one of the most prominent aspects of the results of the current study. Apart from circulating miRNAs, the experimental research literature in other areas is consistent with the findings of the present study. Studies have indicated that microRNAs can regulate multiple signaling pathways involved in the development of pulmonary arterial hypertension (PAH), including endothelin-1, TGF-β/Smad, and Wnt/β-catenin. Some potential miRNAs, such as miR-21, miR-143/145, and miR-204/211, have been cited as relevant to PAH, further substantiating the relationships and signaling pathways mediated by the miRNAs highlighted in the current study.¹⁸ In summary, the relevant experimental research literature serves to validate the results of the current study and provides additional details and evidence to support the discourse on the significant role and potential of miRNAs in the field of hypertension.

Figure 2. Annual publications between 2005–2023.

Study subject analysis

Country/Region distribution

Seventy-one countries participated in research on miRNAs in hypertension. Data were exported using the VOSviewer software, and the geographic distributions of publications on miRNAs in hypertension were mapped using Scimago Graphica software. According to the global map distribution (Figure 3a), the top three countries for publications were China (699, 46.79%), the USA (347, 23.22%), and Germany (71, 0.05%). Countries or regions that published more than 50 papers included England and Italy. These regions are hot spots in the field of miRNA research in hypertension. Figure 3b depicts the publication trends for the top 10 countries since 2005.

Figure 3. Geographic distribution of miRNA research publications in hypertensive.(A) global map based on the total publications of different countries/regions. (B) the countries/regions’ citation network visualization map generated by using Scimago Graphica.

Although China topped the list of publications in recent years, the United States ranks first in total citations (14,924), surpassing China, which ranks second (12,726) (Figure 3b). This indicates that research on miRNAs in hypertension has a high level of authority in the United States and is widely recognized by the academic community. The top 10 countries or regions with the highest number of publications are listed in Table 1. Europe was not only one of the earliest countries and regions to conduct miRNA studies on hypertension, but the average frequency of citations in many other countries, including England, Germany, and Italy, was also at the forefront. This suggests that these countries or regions have a significant impact on miRNA studies in hypertension. In addition, according to Table 1, the total link strength of the United States ranked first, indicating that it had the closest cooperation with many countries.

Table 1. The top 10 countries related to microRNA in hypertension research.

Rank	Country	Publications	Percentage	Citations	Average citations
1	China	699	46.79%	12726	18.21
2	United states	347	23.23%	14924	43.01
3	Germany	71	4.75%	3124	44.00
4	England	70	4.69%	3409	48.70
5	Italy	69	4.62%	3179	46.07
6	India	42	2.81%	1046	24.90
7	Spain	42	2.81%	1204	28.67
8	Australia	41	2.74%	2262	55.17
9	Canada	39	2.61%	2202	56.46
10	Brazil	36	2.41%	786	21.83

Institutions

To present a clear overview of institutional cooperation, a cooperation network map of high-yield institutions with more than 10 papers was presented using the VOSviewer software (Figure 4). In the network map, a node represents an institution, and the size of the node is positively correlated with the number of publications published by the institution. The larger the node, the more publications, and the thickness of the connections between the nodes indicates the strength of the connections.¹⁹

Figure 4. Visualization map of cooperation network between high-yield institutions of miRNA in hypertensive from 2005 to 2023. The size of the circle represents the weight of the connection and the thickness of the connection represents the number of cooperation.

Nanjing Medical University is the most productive and cooperative university, and has published 41 papers among the top 10 institutions in this research field (Table 2). Shanghai Jiao Tong University ranked second with 38 published papers, followed by Xi’an Jiao Tong University and Capital Medical University, which published more than 30 papers, indicating that these institutions had an important influence in this research field.

Table 2. The top 10 institutions related to microRNA in hypertension research.

Rank	Institution	Publications	Citations	Total link strength
1	nanjing med univ	41	831	24
2	shanghai jiao tong univ	38	824	24
3	xi an jiao tong univ	36	677	21
4	capital med univ	32	900	23
5	harbin med univ	25	686	9
6	china med univ	23	310	5
7	chinese acad med sci	22	732	41
8	huazhong univ sci & technol	22	386	10
9	chinese acad sci	21	997	34
10	fudan univ	21	819	21

Research hotspot analysis

Keywords

Keywords are highly condensed representations of features relevant to scientific research that can reflect hotspots within a field and the links between them.²⁰ CiteSpace was used to generate a high-frequency keyword co-occurrence map, as shown in Figure 5. The larger the node in the figure, the more frequent the co-occurrence of keywords, which also represents a hot topic in the research field.²¹ As shown in Table 3, the most frequent keyword in this study was “blood pressure,” with an intermediate centrality of 0.36. This was the primary research focus in this field and aligned with the theme of the article. Followed by “risk,” “expression,” “circulating microRNA,” “cell,” etc., the co-occurrence frequency of other keywords was low, and the research was not in-depth enough, indicating that the research direction is still in an emerging stage and the research prospects are broad. Centrality is a metric used to gauge the importance of nodes within a network, and reflects their positions and roles within the network. Different types of centralities provide insights into the importance of nodes from various perspectives. For example, degree centrality reflects the number of connections a node has with other nodes; closeness centrality reflects the average distance of a node to other nodes; and betweenness centrality reflects the proportion of paths a node occupies between other nodes. In general, higher centrality indicates greater importance. In this study, we used the betweenness centrality metric provided by CiteSpace software to evaluate the importance of nodes, such as literature and keywords, within the network. Readers can assess the centrality by observing the size of the nodes in a network graph, with larger nodes indicating higher centrality and greater importance.

Figure 5. High-frequency keyword co-occurrence map of microRNA in hypertension research from 2005 to 2023.2023.The size of circle refers to the number of articles. The thickness of the outer pink circle represents the size of centrality.

Table 3. The top 10 keywords related to microRNA in hypertension research.

Rank	Publications	Centrality	Starting Year	Keywords
1	179	0.36	2008	blood pressure
2	66	0.25	2008	risk
3	450	0.22	2008	expression
4	139	0.08	2011	circulating microrna
5	151	0.08	2006	cell
6	126	0.08	2011	cancer
7	124	0.08	2009	growth
8	304	0.06	2008	biomarker
9	284	0.05	2008	gene expression
10	145	0.05	2012	smooth muscle cell

The keyword clustering network is based on the co-occurrence graph, and the log-likelihood ratio (LLR) algorithm was used to analyze the structural characteristics, key nodes, and degree of connectivity among clusters in the clustering view. High-frequency words were used to reflect the hotspots and dynamic changes in this research field in different years.²² As shown in Figure 6, the time slice was set to one year, the top 25 most-cited papers were selected from each area, and all extracted keywords were classified using CiteSpace. Generally, a clustering module value (Q-value) greater than 0.3 is considered to indicate a significant clustering structure. Additionally, when the average silhouette value (S-value) was greater than 0.7, the clustering was considered convincing.²³ In this study, the clustering results indicated a high level of credibility with a Q-value of 0.7113 (>0.3) and an average S-value of 0.8993 (>0.7).²³ The clustering network resulted in ten clusters, which were further categorized into seven major classifications based on the synthesis and organization of keywords within each cluster. The analysis was performed as follows.

Figure 6. The cluster network of high-frequency keywords.

Class I (#0, #7) Study on the correlation between coronary heart disease and hypertension Coronary heart disease (CAD) is a myocardial ischemic disease, which can cause chest pain, shortness of breath, shortness of breath, palpitations, and other symptoms. In particular, patients with unstable angina pectoris have more severe symptoms and significant differences in pathogenesis and stable angina pectoris.²⁴ Blood pressure as a CAD risk factor has complex pathophysiological mechanisms, including the effect of blood pressure as a physical force on atherosclerotic plaque development and the interplay between pulsatile hemodynamics, arterial stiffness, and coronary artery perfusion.²⁵ Diastolic blood pressure (DBP) is one of the determining factors for coronary blood flow (CBF).^26,27 Additionally, left ventricular perfusion occurs primarily during diastole. In the presence of left ventricular hypertrophy and epicardial coronary artery stenosis, low diastolic blood pressure may lead to a relative decrease in CBF, thereby impairing the autoregulatory function of the coronary arteries.²⁸ Thus, the goal of blood measurement in patients raises controversial. A recent study developed a patient-specific algorithm using three determinants of CBF to guide therapy by considering the degree of coronary artery stenosis, left ventricular mass, and DBP to avoid excessive reduction of coronary blood flow to reduce the likelihood of myocardial ischemia, and thus individualize blood pressure management in patients with CAD.²⁹

Class II (#1, # 2, # 6) Study on the correlation between miRNAs and hypertension vascular smooth muscle cells (VSMCs) are major cellular components of arterial mediators.³⁰ that participate in vascular remodeling and control vascular tone under physiological conditions, thereby maintaining blood pressure stability. Under pathological conditions, the VSMC phenotype switches from contractile to synthetic, characterized by cell proliferation, migration, and differentiation, which are changes that disrupt vascular function and can lead to disease progression.^31–33 It has been experimentally confirmed that miRNAs are involved in the development of hypertension through various pathways, including participation in the structural and functional changes of vascular smooth muscle cells and promotion of pathological changes in blood vessels.³³ Overexpression of miR-145 or inhibition of miR-146a expression in rats inhibits vascular smooth muscle cell proliferation and differentiation by downregulating KLF5 expression or promoting KLF4 expression, respectively, and reduces vascular intimal hyperplasia after balloon injury in rat carotid arteries.^34,35 Additionally, silencing miR-135a-5p attenuates VSMC proliferation and vascular remodeling in SHR by inhibiting the transcription of FNDC5, indicating that the inhibition of miR-135a-5p expression may be a therapeutic approach to attenuate vascular remodeling and hypertension.³⁶

Angiotensin II(Ang II) exerts vasoconstrictive effects and induces vascular remodeling and proliferation of vascular smooth muscle cells, leading to increased blood pressure.^37,38 Xu et al..³⁹ found that overexpressed miR-27a promoted Ang II-induced VSMC proliferation and migration by targeting α-smooth muscle actin (α-SMA); in contrast, knockdown of miR-27a inhibited this effect, indicating that miR-27a emerged as a novel modulator of Ang II-induced VSMC proliferation and migration by directly targeting α-SMA in VSMC. Gu et al.⁴⁰ demonstrated for the first time that miR-16 knockdown promotes Ang II-induced cell proliferation and migration through its involvement in multiple Ang II-related signaling pathways in cardiovascular disease. In addition, VSMC proliferation and miR-130a expression were enhanced by Ang II in a concentration- and time-dependent manner, along with a decrease in the expression of growth arrest-specific homeobox (GAX).⁴¹ This suggests that miR-130a is a novel regulator that promotes VSMC proliferation by inhibiting GAX expression, and contributes to vascular remodeling in hypertension. The results of these two studies suggest that miRNAs that enhance the anti-apoptotic effect of VSMC by participating in Ang II signaling channels may provide a new perspective for the treatment of hypertensive diseases.

Class III (#3) Study on the correlation between circulating microRNAs and hypertension Since the discovery of miRNAs, more than 2,000 miRNAs have been discovered, and these miRNAs regulate nearly one-third of genes.⁴² Because miRNAs were originally identified in intracellular locations, they are regarded as key endogenous regulators of intracellular processes; however, recent studies have shown that they can migrate extracellularly and enter body fluids and are called circulating microRNAs.⁴³ It is characterized by high specificity, easy accessibility, and high sensitivity.⁴⁴ Owing to these characteristics, they are often used as diagnostic and prognostic biomarkers for many cardiovascular diseases, including hypertension.⁴⁵ In a study investigating the correlation between human cytomegalovirus and hypertension, 27 differentially expressed circulating miRNAs were identified in 13 patients with primary hypertension and five healthy control subjects.⁴⁶ Another study found that miR-505 in the plasma was significantly upregulated in patients with hypertension, and further investigation of the mechanism revealed that endothelial inflammation activation could be promoted in a cell-autonomous manner to mediate endothelial dysfunction in vivo, which in turn led to increased blood pressure. Therefore, circulating miR-505 is regarded as a prognostic biomarker of hypertension.⁴⁷

Class IV (#4) study on the correlation between cardiac remodeling and hypertension Patients with hypertension activate the neuroendocrine system due to increased blood pressure, leading to changes in the gene expression of cardiomyocytes, non-cardiomyocytes, and the extracellular matrix; thus, the cardiac structure, metabolism, and function undergo a long-term pattern remodeling process known as cardiac remodeling.⁴⁸ Overactivation of the renin-angiotensin system (RAS) has been found to be closely associated with the development of cardiac remodeling in hypertension.⁴⁹ In the RAS cascade pathway, angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I (Ang I) to Ang II. Ang II then binds to the Ang II type 1 receptor (AT1R) to form the ACE-Ang II-AT1R axis, which in turn leads to oxidative stress and proinflammatory responses, thereby causing pathological cardiac remodeling, such as myocardial hypertrophy and interstitial fibrosis, ultimately leading to cardiac decompensation and heart failure.^50,51 In addition, there is a counter-regulatory mechanism for the RAS, namely ACE2. ACE2 shifts Ang I or Ang II to Ang (1–7), which binds to the Mas receptor and mediates biological actions that counteract many adverse effects of the ACE-Ang II-AT1R axis.⁵² It has been confirmed that an imbalance between the ACE-Ang II-AT1R and ACE2-Ang (1–7) -Mas receptor axes is an important marker of chronic hypertension, which can lead to cardiac dysfunction and target organ damage, whereas inhibition of the ACE-Ang II-AT1R axis or activation of the ACE2-Ang (1–7) -Mas receptor axis has cardioprotective effects. This study provides a new perspective for the treatment of hypertensive cardiac remodeling.

Class V (#5) Salt-sensitive hypertension Many hypertension model studies and epidemiology have confirmed that excessive sodium intake is a critical environmental factor in the occurrence and development of primary hypertension. Individuals within the population, however, respond differently to salt load or salt restriction in terms of blood pressure; that is, there are salt sensitivity problems. In 1960, Dahl.⁵³ developed a rat model of hereditary salt-sensitive hypertension. Subsequently, Kawasaki.⁵⁴ and Luft.⁵⁵ proposed the concept of “salt-sensitive hypertension” based on the blood pressure response to high dietary salt intake in hypertensive and normotensive individuals, respectively. Currently, there are no standard criteria for the assessment of salt-sensitive hypertension. This is because it is not possible to identify precise cutoff points for individual classification. Based on this, some studies have proposed cutoff points for salt sensitivity. For individuals with normal blood pressure, a change of at least 3–5 mmHg in the mean arterial pressure (MAP) is considered indicative of salt sensitivity. For individuals with hypertension, a change of at least 8–10 mmHg in MAP is considered indicative of salt sensitivity.⁵⁶ However, as assessing sodium intake through dietary assessment is prone to recall bias, further exploration is needed to identify alternative methods for confirming sodium intake.

Class VI (# 8) Developmental Origins Increasing epidemiological and experimental evidence suggests that adult-onset hypertension may originate during early development.⁵⁷ Nutrition is a major environmental factor in utero that alters fetal morphology and function through a process called fetal programming.⁵⁸ The adverse factors involved in this process may contribute to future hypertension.⁵⁹ The phenomenon in which adverse conditions during development increase susceptibility to disease in adults has been named the “developmental origins of health and disease”.⁶⁰ This concept suggests that theoretical approaches to the treatment of diseases shift from adult life to early stages, potentially reversing the disease process before the clinical disease becomes apparent.^61,62

Class VII (# 9) Study on the correlation between insulin and hypertension Insulin is a classic metabolic regulatory hormone that is indispensable for controlling the body’s metabolism of lipids and glucose. Recent studies have shown that insulin resistance is a key component of the pathogenesis of hypertension.⁶³ One study found that spontaneously hypertensive rats (SHR) had insulin resistance in the blood vessels, and 4-week-old juvenile SHR showed decreased vascular insulin sensitivity before increased blood pressure and an imbalance in vascular insulin signaling pathways, that is, decreased activation of Akt-eNOS-NO and increased extracellular signal-regulated kinase 1/2-endothelin-1 signaling, suggesting that vascular insulin resistance occurs before the formation of hypertension and promotes the occurrence and progression of hypertension.⁶⁴ Another study showed that myocardial positive inotropic effects induced by insulin and calcium transients that underlie contractile function were significantly attenuated in SHR compared with normal rats, a mechanism related to reduced Akt-eNOS activation and its upstream signaling molecule peroxisome proliferator-activated receptor γ (PPARγ) associated with decreased PI3K expression in SHR cardiomyocytes.⁶⁵

Literature

Literature clustering analysis was performed using CiteSpace software with time slices set to two years, and clusters were formed by extracting the first ten high-frequency cited studies. The high-frequency literature was categorized into seven specific clusters, as shown in Figure 7. The average modularity (Q) and silhouette (S) values for clustering were 0.8193 and 0.9592, respectively. These values indicated a good overall clustering effect. After integrating the clustering content, the seven clusters were categorized into five major groups.

Figure 7. Cluster of co-citation document network.

Class I (#0) Functional Genomics Since the human genome was sequenced in 2000, research patterns in the biomedical field have changed rapidly. With an increasing understanding of the genome structure and changes, scientists have been able to study thousands of genes simultaneously. This makes the biomedical community no longer limited to testing the function of a single gene, but to studying many or even all genes in a balanced state in a less biased manner. This type of research falls within the broad category of “functional genomics,” which can be defined as a branch of biology that aims to reveal the characteristics and functions of all genes and gene products within an organism.⁶⁶ Functional genomics is driving the rapid development of biomedicine, and the discovery of new pathogens and drug targets through unbiased genome-wide screening is currently a research hotspot.⁶⁷ Chen et al..⁶⁸ conducted a transcriptomic screening of the myocardium of patients with left ventricular dysfunction before and after treatment with a ventricular assist device. They discovered that the APJ receptor was an important novel cardiovascular regulatory mediator. Further research has shown that apelin, as the natural ligand for APJ, is highly expressed in patients with chronic heart failure. Consequently, apelin has been identified as a therapeutic target in chronic heart failure.⁶⁹

Class II (#1) Cardiac hypertrophy cardiac hypertrophy refers to changes in cardiac volume resulting from unchanged cardiomyocyte numbers, but increased cardiac volume in response to increased cardiac preload or afterload to maintain perfusion in peripheral organs to meet their normal or stressful conditions.⁷⁰ There are two main types of hypertrophy, physiological and pathological. Physiological hypertrophy of the heart usually occurs during growth in children, pregnancy in women, and exercise and is reversible.^71,72 Pathological hypertrophy is caused by long-term and abnormal hemodynamic responses, hypertension, myocardial infarction, and other factors, ultimately leading to heart failure and even sudden death.⁷³, and is pathologically characterized by a larger ventricular volume accompanied by myocardial dysfunction and fibrosis.⁷⁴ In terms of therapeutic intervention, ACE and sympathetic inhibitors have achieved good clinical results.⁷⁵ However, this approach is not suitable for all patients. This may be because cardiac hypertrophy, which is an adaptive response disease, does not need to be completely suppressed.^75,76 Therefore, the pathological mechanism involved in cardiac hypertrophy should be studied and analyzed in the future. The drug dose should be carefully designed, and targeted treatment should be performed to block harmful consequences while maintaining the balance of the heart.

Class III (#2) microRNA-155 miR-155 is a multifunctional RNA encoded by exon 3 of the BIC gene located on chromosome 21 in humans and is abundantly expressed in the human spleen, thymus, liver, lungs, and kidneys.⁷⁷ It is mainly involved in biological processes such as the development, differentiation, activation, proliferation, and immune response of immune cells.⁷⁸ miR-155 is a critical modulator of the immune effector stages of pathogen clearance and apoptotic cells.⁷⁹ is essential for maintaining B-cell function.⁸⁰, overexpression of miR-155 promotes pre-B-cell proliferation, and may lead to B-cell lymphoma.⁸¹ Glucocorticoids have also been found to attenuate lipopolysaccharide (LPS) -induced inflammatory responses and sepsis by downregulating miR-155 expression. The anti-inflammatory effects of glucocorticoids can be reversed by inhibiting miR-155 expression; thus, steroid inhibition of miR-155 may be a novel functional pathway in immune responses.⁸²

Class IV (#3, #4, #5) Extracellular vesicles as novel biomarkers of cardiovascular disease Extracellular vesicles (EV) refer to the collective term for small membrane-bound vesicles released by cells.⁸³, which are formed or activated by parent cells under the influence of different factors such as inflammation, hypoxia, oxidative stress, aging, and apoptosis.⁸⁴ Various cells, including immune cells, mesenchymal stem cells, and blood cells, can secrete EV; thus, they are widely distributed in various body fluids, such as blood, urine, and milk, and exert specific biological functions. In addition, they can dynamically reflect disease states by carrying specific substances from blasts such as proteins, miRNAs, mRNAs, lncRNAs, and lipids.^84,85 Therefore, EVs are considered novel biomarkers for the diagnosis and monitoring of disease status in humans.⁸⁶ EV has been found to be involved in the development of hypertension by mediating vascular dysfunction, renal sodium and water transporter abnormalities, and RAS disturbances.⁸⁷ Meanwhile, it has also been shown that intracoronary injection of EV derived from cardiosphere-derived cells can reduce myocardial wall injury in acute myocardial infarction in rats and pigs.⁸⁸ These EVs provide new ideas for the future treatment of cardiovascular diseases.

Class V (#6) SNP-guided microRNA map single-nucleotide polymorphism (SNP)-guided miRNA map refers to genetic variation in the DNA sequence of a genome caused by the conversion, deletion, insertion, or substitution of a single nucleotide base in a gene. This type of polymorphism is commonly found in the genes of various organisms.⁸⁹ Over the past decade, several new DNA molecular labeling systems have been established with the development of DNA molecular labeling technologies. Currently, SNP markers are among the most widely used genetic markers. Polymorphisms in miRNA regulatory pathways are novel functional polymorphisms; however, because of the complexity of miRNA generation and the impact of miRNAs on the entire genome, the biological functions of miRNA SNPs have not yet been clearly explained.⁹⁰ Sequence changes in the 3 “UTR region of target genes are more abundant in the human genome compared to polymorphisms during miRNA transcription. The 3” UTR region is a critical control region with the ability to regulate m RNA stability, translation, and localization. On the other hand, SNPs within miRNA target sites only affect the target mRNA and its downstream effector and are therefore more specific. Luo et al..⁹¹ demonstrated that a single nucleotide polymorphism (1010A/G) located within the micro-RNA-7 binding site in the 3 “UTR region of the HOXB5 gene affected HOXB5 gene expression in bladder cancer mainly through differential binding activity of micro-RNA-7 and m RNA stability associated with single nucleotide polymorphisms. SNP rs 12 607 853 in the 3′-untranslated regions (3′-UTR) of the has-miR-422a target gene DCC at its target site is significantly associated with heroin addiction.⁹², and has-miR-1270 binds allele-specific to alleles at SNP sites to inhibit luciferase activity, to SNPs in the 3” UTR of the gene to inhibit transporter associated with antigen processing 2 (TAP2) gene production, and can also regulate TAP2 gene expression by targeting cognitive sequences containing the T allele of rs 241 456.⁹³ Exploring SNPs associated with mi RNA and their association with phenotypic traits can provide insights into the regulatory mechanisms and functions of miRNAs.

Literature source and knowledge distribution characteristics

Journals

Screening and summarizing the articles published by the Top10 can directly reflect the main journal sources of relevant research literature in this field and help researchers quickly and effectively conduct literature inquiry, data acquisition, and paper submission. As shown in Table 4, between 2005 and 2023, the journal with the highest number of international publications was the International Journal of Molecular Sciences, but the recent IF, total frequency of citations, frequency of citations per paper, and the H-index did not rank first, indicating that the academic influence of this journal was insufficient, and the comprehensive influence of this publishing platform in the research field of miRNAs in hypertension needs to be significantly improved. The journal PLOS ONE has the second highest publication volume in the field, with a journal citation report (JCR) quartile ranking of Q2. It ranked first in terms of H-index, total frequency of citations, and frequency of citations per paper. Although its IF was slightly lower, it was considered one of the highest-quality international English journals with a significant level of influence.

Table 4. The top 10 journals related to microRNA in hypertension research.

Rank	Journal	Count	TC	TC/P	JCR	IF(2022)	H-factor(2022)
1	international journal of molecular sciences	46	1105	24.02	Q1	6.208	114
2	plos one	45	1204	26.76	Q2	3.752	268
3	hypertension	40	2128	53.20	Q1	9.897	246
4	scientific reports	29	668	23.03	Q2	4.996	149
5	experimental and therapeutic medicine	23	199	8.65	Q4	2.751	33
6	molecular medicine reports	21	324	15.43	Q3	3.423	43
7	biomed research international	17	298	17.53	Q3	3.246	94
8	clinical and experimental hypertension	17	284	16.71	Q4	2.008	45
9	frontiers in cardiovascular medicine	17	336	19.76	Q3	2.877	91
10	current hypertension reports	15	504	33.60	Q2	4.592	63

Authors

VOSviewer was used to draw a visual map of the main author cooperation network for high-yielding authors with more than five papers, as shown in Figure 8. Table 5 summarizes the statistical characteristics of the top 10 high-yielding authors, including publications, institutions, and countries. Liang Mingyu had the highest number of publications, with 20 papers. Hromadnikova, Ilona, Kotlabova, Katerina, and Krofta, Ladislav were tied in second place with 17 papers each. Other authors who have published over 10 papers include Liu, Yong, Bonnet, Sebastien, Gou, Deming, Thum, Thomas, Zhang, and Lina. As shown in Table 5, the majority of the top 10 prolific authors in this field became active and achieved significant accomplishments after 2010. Thus, the past decade has been a crucial period in this field of research.

Figure 8. Visualization map of main author cooperation network of microRNA in hypertension research from 2005 to 2023. The size of the circle refers to the number of articles published by the author.

Table 5. The top 10 authors related to microRNA in hypertension research.

Rank	author	Documents	Country	Institution	Year
1	liang, mingyu	20	America	Medical College of Wisconsin	2008
2	hromadnikova, ilona	17	Czech Republic	Charles University	2015
3	kotlabova, katerina	17	Czech Republic	Charles University	2015
4	krofta, ladislav	17	Czech Republic	Charles University	2015
5	liu, yong	15	America	Medical College of Wisconsin	2010
6	bonnet, sebastien	12	Canada	Laval University	2011
7	gou, deming	11	China	Shenzhen University	2012
8	thum, thomas	10	Hannover	Hannover Medical School	2015
9	zhang, lina	10	China	Medical School of Ningbo UniversityUniversity	2019
10	charchar, fadi j.	9	Australia	Federation University Australia	2011

Conclusions and outlook

This study utilized the WOS Core Collection database and employed CiteSpace and VOSviewer analysis software to conduct a visual analysis of miRNA research in hypertension, based on literature published between 2005 and 2023. This study presented the institutions conducting miRNA research in hypertension and explored the research hotspots in the field, characteristics of literature sources, and knowledge distribution. The following conclusions were drawn.

1. Research on the involvement of miRNAs in hypertension has attracted the attention of researchers. Between 1990 and 2021, the global volume of research publications in the field of miRNAs exhibited an overall increasing trend. Variations in publication volume during different periods can be closely associated with the research stage and the medical conditions prevailing in the field at that time.

2. From the distribution of institutions, China, the United States, and Germany contributed the most to this research field. Among these, the United States had the closest collaboration with many countries. Nanjing Medical University has made the greatest contribution to the research field in terms of its institutional distribution.

3. Analysis of the research hotspots reveals two main aspects. First, based on keyword co-occurrence analysis, important topics in the research field included blood pressure, risk, expression, and circulating microRNAs and cells. Second, through keyword clustering analysis and further consolidation, these topics were categorized into seven major themes: correlation between coronary heart disease and hypertension, correlation between miRNAs and hypertension, correlation between circulating microRNAs and hypertension, correlation between cardiac remodeling and hypertension, salt-sensitive hypertension, developmental origins, and correlation between insulin and hypertension. These seven classifications reflect popular topics in the research field. Through cluster analysis of the cited literature, five clusters were identified, revealing the research hotspots of miRNAs in hypertension, including functional genomics, cardiac hypertrophy, microRNA-155, extracellular vesicles as novel biomarkers for cardiovascular diseases, and an SNP-guided microRNA map.

4. From the literature sources and knowledge distribution characteristics, the International Journal of Molecular Sciences was the most influential journal in the field, and Liang Mingyu was the author with the largest number of publications.

5. Currently, the research field is experiencing a period of vigorous development, with strong interest from scholars worldwide. China assumes a leading position in international research. However, there is still room for improvement in terms of the collaboration between different institutions and teams. Considering the current situation, it is recommended that research institutions and groups strengthen their cooperation, integrate resources, and strive to standardize the research field by providing more evidence and clarifying the underlying mechanisms.

Based on an analysis using CiteSpace and VOSviewer, this study surpasses traditional research methods and provides a more intuitive representation of research content and field hotspots. It also facilitates the prediction of future research directions based on the analytical results. However, this study has certain limitations. This study has several limitations. First, it relied exclusively on the WOS database, potentially causing incomplete coverage and selection bias by overlooking relevant literature in other databases. Second, the study utilized CiteSpace and VOSviewer software for bibliometric analysis and visualization, which may not effectively handle Chinese literature, depend on manual selection, and lack an assessment of literature quality or impact. Third, the methods employed for keyword co-occurrence analysis and literature clustering have constraints in representing causal relationships, distinguishing subtopics, and considering temporal changes. These limitations may affect the accuracy and applicability of our findings. To enhance scientific robustness, future research should consider the following steps. (1) Broaden data sources by searching multiple databases and facilitating data comparison and integration. (2) Employing a variety of software tools and methodologies, allowing for the comparison and validation of results. (3) Use advanced analytical techniques complemented by experimental or theoretical validation to support the analysis outcomes.

This study conducted a comprehensive visual analysis of miRNA research in the field of hypertension, revealing the research landscape, hotspots, developmental trends, and future directions in this domain. This study highlights the pivotal regulatory roles of miRNAs in the onset and progression of HTN. miRNAs influence various aspects, including vascular function, myocardial remodeling, and renal sodium balance, by participating in multiple signaling pathways and modulating target gene expression. MicroRNAs (miRNAs) have enormous potential as biomarkers and therapeutic targets for hypertension, especially circulating miRNAs and miRNA polymorphisms. These findings offer valuable insights and guidance to researchers and clinicians in the field of hypertension, facilitating a deeper understanding of the pathogenesis of hypertension, selection of effective biomarkers, and design of personalized treatment strategies.

Authors’ contributions

Conceived the idea and conceptualized the study:Yu Sun, Qingxin Shang

Collected the data: Yu Sun

Analyzed the data:Yu Sun, Qingxin Shang

Drafted the manuscript:Yu Sun

Reviewed the manuscript:Yu Sun, Qingxin Shang

All authors read and approved the final draft.

Ethics approval and consent to participate

This study is a literature review and does not require the informed consent of patients, and does not require ethical approval.

Acknowledgments

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.