
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12358-4
10.1016/j.heliyon.2024.e36327
e36327
Research Article
Comparative efficacy of the five most common traditional Chinese medicine monomers in reducing intimal hyperproliferation in arterial balloon injury models: A network meta-analysis
Xie Long a
Mao Tianshi a
Gao Qun a
Pan Yi a
Yang Zhifei b
Qu Xinyan a
Feng Ruli a
Xia Junyan a
Lin Qian linqian62@126.com
a⁎
Wan Jie Yuezhijie1226@sina.com
b⁎⁎
a Department of Cardiology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100029, China
b Department of Cardiology, Dongfang Hospital Beijing University of Chinese Medicine, Beijing, 100029, China
⁎ Corresponding author. Department of Cardiology, Dongzhimen Hospital Beijing University of Chinese Medicine, No.5, Haiyuncang, Dongcheng District, 100700, Beijing, China. linqian62@126.com
⁎⁎ Corresponding author. Department of Cardiology, Dongfang Hospital Beijing University of Chinese Medicine, No.6, Fangxing Yuan I, Fengtai District, 100078, Beijing, China. Yuezhijie1226@sina.com
19 8 2024
15 9 2024
19 8 2024
10 17 e3632724 4 2024
13 8 2024
13 8 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Objective

This study utilized network meta-analysis (NMA) to compare the efficacy of five commonly used traditional Chinese medicine monomers in reducing intimal hyperproliferation in arterial balloon injury models.

Methods

Relevant literature up to January 2024 was systematically retrieved from seven major databases. The intima-to-media (I/M) ratio was chosen as the primary outcome measure. The risk of bias in animal studies was assessed using the SYstematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. Statistical analysis was conducted using Stata 17 software.

Results

A total of 43 studies were included in this meta-analysis. NMA results showed that in the rat model, compared to the control group, GS (SMD: 0.99, 95%CI: 1.25 to −0.73), ASIV (SMD: 1.16, 95%CI: 1.65 to −0.67), TMP (SMD: 0.68, 95%CI: 1.31 to −0.05), and TPNS (SMD: 1.36, 95%CI: 1.91 to −0.80) exhibited inhibitory effects on postoperative intimal hyperproliferation, reducing the I/M ratio. In the rabbit model, compared to the control group, TPNS (SMD: 1.23, 95%CI: 1.97 to −0.49) inhibited postoperative intimal hyperproliferation and reduced the I/M ratio. Superiority ranking analysis suggested that total Panax notoginseng saponin (TPNS) might be the most effective traditional Chinese medicine monomer in reducing intimal hyperproliferation in arterial balloon injury models, lowering the I/M ratio.

Conclusion

NMA indicates that traditional Chinese medicine monomers can effectively reduce postoperative intimal hyperproliferation in arterial balloon injury models, lowering the I/M ratio, with TPNS showing optimal efficacy. However, the research on TIIA is insufficient, and the limited sample size may affect the robustness of the results. Furthermore, the majority of research on traditional Chinese medicine monomers is currently limited to the experimental stage, lacking further clinical validation. Conducting standardized animal experiments and reporting their findings can enhance the quality of evidence from animal studies, laying the foundation for future clinical trials.

Keywords

Traditional Chinese medicine monomers
Balloon injury
Intima-to-media ratio
Animal studies
Network meta-analysis
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pmc1 Introduction

Percutaneous coronary intervention (PCI) is a crucial means of coronary artery revascularization for coronary heart diseases. Despite rigorous pharmacological interventions following recommended guidelines, the incidence of 30-day major adverse cardiovascular events (MACE) remains 6–7%, and the overall MACE rate at 2 years can escalate to 35.8 % [1]. Among the numerous mechanisms underlying the occurrence of post-PCI MACE, restenosis remains one of the most critical factors. During an interventional procedure, balloon-induced mechanical injury and integrity loss to the vascular intima, vascular smooth muscle cell (VSMC) migration, proliferation, and extracellular matrix (ECM) accumulation can lead to neointimal thickening, resulting in luminal narrowing and impacting long-term prognosis for patients [2,3]. Numerous arterial balloon injury models have been employed to assess post-PCI restenosis, among which small-to medium-sized animal models offer several benefits. This includes cost-effectiveness, rapid development of the pathological process after injury, more convenient manipulation without needing a catheterization lab, and enhanced evaluation of luminal stenosis caused by VSMC proliferation [4].

The application of traditional Chinese medicine (TCM) in patients who have undergone PCI has been shown to effectively reduce the late luminal loss rate [5]. The expanding research on TCM monomers has discovered that these components exhibit higher biological activity and specific drug targets. Some of these herbal monomers have been demonstrated to reduce intimal hyperproliferation in the repair of vascular injury post-PCI, with extensive studies focused on ginsenoside (GS), astragaloside IV (ASIV), tanshinone IIA (TIIA), ligustrazine (tetramethylpyrazine, TMP), and total Panax notoginsenoside (TPNS) [6]. GSs are a class of triterpenoid saponins connected to sugar chains extracted from ginseng, and they are the main active components through which ginseng exerts its pharmacological effects [7]. ASIV is a single component extracted and isolated from the roots of Astragalus. Among various subtypes of astragalosides, ASIV is the most biologically active compound [8]. Tanshinone is a lipophilic component extracted from the Chinese medicinal herb Salvia miltiorrhiza, and TIIA is one of the major active components of tanshinone [9]. TMP is a monomeric alkaloid exhibiting strong structural and functional representation extracted from the roots and rhizomes of the Chinese medicinal herb Ligusticum chuanxiong [10]. Panax notoginseng, widely used in China and other Asian countries, has its primary pharmacologically active component as total Panax notoginsenoside (TPNS) [11]. Numerous animal studies have consistently demonstrated that the above five herbal monomers exert inhibitory effects on excessive VSMC proliferation following balloon injury through different mechanisms. However, it remains unclear which monomer exhibits the most significant inhibitory effect. Therefore, this study employed a network meta-analysis (NMA) to assess the efficacy of the five most common herbal monomers in reducing intimal hyperproliferation in arterial balloon injury models. The study provides a foundation for future animal study designs and theoretical support for herbal monotherapy in treating post-PCI restenosis.

2 Materials and methods

2.1 Registration

This research protocol has been registered with INPLASY (Registration Number: INPLASY 202410054). The design, execution, analysis, and reporting of this study adhere to the criteria outlined in the PRISMA statement [12].

2.2 Search strategy

We conducted searches in databases including PubMed, Web of Science, Ovid-Embase, CNKI (China National Knowledge Infrastructure), Wanfang Data, VIP (Chinese Scientific Journals Full-text Database), and CBM (Chinese Biomedical Literature Database). The search period extended from the establishment of the databases to January 2024. We utilized a combination of controlled vocabulary, keywords, free-text terms, or Medical Subject Headings (MeSH) terms to comprehensively identify potentially eligible papers. These terms included “carotid artery balloon injury,” “angioplasty,” “carotid artery,” “balloon injury,” “balloon,” “ginsenoside,” “astragaloside IV,” “tanshinone IIA,” “ligustrazine,” and “total panax notoginsenoside.” We adjusted the search strategies accordingly for each database.

Detailed search strategies for each database are available in the supplementary materials. There were no restrictions on blinding, language, or publication year.

2.3 Inclusion and exclusion criteria

The inclusion criteria for the studies are as follows: (1) Animal: Arterial balloon injury model animals; (2) Intervention: 5 herbal monomers (GS, ASIV, TIIA, TMP, TPNS); (3) Control: Placebo or untreated; (4) Outcome: Intima-to-media ratio (I/M) after arterial balloon injury (the ratio of intima-to-media area or the ratio of intima-to-media thickness); (5) Study type: Controlled studies.

Exclusion criteria: (1) Other models of arterial injury caused by different reasons, such as arterial ligation model or drug-induced arterial injury; (2) Studies that did not report intima-to-media ratio; (3) Duplicate publications; (4) Studies that did not provide complete raw data or were unable to extract data.

2.4 Data extraction and quality assessment

Data extraction was independently conducted by two trained researchers. After screening the papers based on inclusion/exclusion criteria to determine the final inclusion of literature, the results of the screening were cross-checked. In case of discrepancies, consultation with a third researcher was undertaken for resolution. Basic data were extracted according to a standard checklist, including author, publication year, country, study design, species, age, gender, weight, sample size, balloon type, type of herbal monomers, dosage and administration, and outcome measures: intima-to-media ratio.

To assess the quality of the studies, we utilized the SYRCLE tool for assessing the risk of bias in animal studies [13]. This process was independently carried out by researchers, and any disagreements were resolved through consultation with a third researcher. The quality of the studies was evaluated as “low,” “high,” or “unclear” risk.

2.5 Statistical analysis

NMA was conducted using a Bayesian model based on the Markov chain Monte Carlo method [14]. Since the data included in this study are all continuous variables, the effect size was represented using the standardized mean difference (SMD), with a confidence interval (CI) set at 95 %. When the 95%CI of the SMD did not include zero, the difference between the two groups was considered statistically significant. Considering the heterogeneity of different study designs, a random effects model was chosen for data synthesis. A network plot was employed to compare the relationships between the five herbal monomers and sample sizes. The Surface Under the Cumulative Ranking (SUCRA) was used to rank the probabilities of the five herbal monomers [15]. It represents the percentage of efficacy achieved by a drug compared to the hypothetical best drug in the absence of uncertainty. Higher SUCRA scores indicate better efficacy. Additionally, a funnel plot was used to assess publication bias and small sample effects. All analyses were conducted using STATA software (version 15, Stata Corporation, TX, USA).

3 Results

3.1 Results of literature search

A total of 1450 articles were identified through the database search. After excluding irrelevant literature and duplicate articles according to the exclusion criteria, a final set of 34 articles, comprising 43 studies, was included in the analysis. The detailed screening process is illustrated in Fig. 1.Fig. 1 Flowchart of the study selection process.

Fig. 1

3.2 Basic characteristics of literature

This study ultimately included 43 randomized controlled trials and 3 controlled studies, comprising 601 animals with 320 in the experimental group and 281 in the control group. All animals received one of the five herbal monomers after arterial balloon injury. Thirty-seven studies used Sprague−Dawley (SD) rats as animal models, whereas six studies used New Zealand white rabbits. The experiments were all conducted in China. The weight of the rats ranged between 250 g and 400 g, whereas that of the rabbits ranged from 1.6 to 3.0 kg. Fig. 2(A–D) and Supplementary Table 2 show the main characteristics of the included studies.Fig. 2 Basic information for inclusion in the study. (A) Types of studies; (B) Types of balloon; (C) Types of medications; (D) Administration route.

Fig. 2

3.3 Risk of bias

Utilizing SYstematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool's strict evaluation of the bias risk in the included studies, only 6 (13.95 %) of the 43 included studies used random number table randomization, with 33 (76.74 %) studies only stating randomization without specifying the randomization method, and 4 (9.3 %) studies not mentioning randomization. In 31 (72.09 %) studies, the baseline characteristics of experimental animals (gender, age, and weight) were similar, but 12 (27.91 %) studies reported potential baseline imbalances in experimental animal values due to randomization of interventions followed by balloon surgery. None of the studies mentioned allocation concealment or any specific feeding methods. The outcome indicators were unlikely to be affected by non-random feeding, so all studies were at low risk. Due to limited information provided by the included studies, no study reported blinding of intervention personnel. Additionally, only one study (2.32 %) reported random measurement of outcome indicators. Blinding of outcome assessors was implemented in three studies (6.98 %). The final analysis of the studies did not exclude any animals, thereby providing complete outcome data. Not all studies provided access to protocols, but all study reports included expected outcomes. The comprehensive details regarding the studies have been provided in Fig. 3.Fig. 3 The risk of bias assessment.

Fig. 3

3.4 Network meta-analysis results

3.4.1 Rat arterial balloon injury model

3.4.1.1 Network evidence map

An NMA was conducted with a final count of 37 studies on rat models. The network evidence graph visually illustrates the absence of direct comparisons between the five herbal monomers. Node size represents the sample size, whereas line thickness represents the number of related studies. As all included studies were controlled trials, the placebo group has the largest node and the most samples. Among the five herbal monomers, most studies focused on GS, followed by TPNS, whereas fewer focused on TMP (Fig. 4).Fig. 4 Evidence network diagram of rat arterial balloon injury model.

Fig. 4

3.4.1.2 NMA results

A total of 37 studies reported the efficacy of different herbal monomers in reducing intimal hyperproliferation in rats with arterial balloon injury (GS vs Placebo (n = 19), ASIV vs Placebo (n = 5), TIIA vs Placebo (n = 4), TMP vs Placebo (n = 3), TPNS vs Placebo (n = 6)). The results showed that the following results: GS vs Placebo (SMD: 0.99, 95 % CI: 1.25 to −0.73), ASIV vs Placebo (SMD: 1.16, 95 % CI: 1.65 to −0.67), TMP vs Placebo (SMD: 0.68, 95 % CI: 1.31 to −0.05), and TPNS vs Placebo (SMD: 1.36, 95 % CI: 1.91 to −0.80). Clearly, compared to the control group, the herbal monomers GS, ASIV, TMP, and TPNS were effective in reducing postoperative intimal hyperproliferation and lower the I/M ratio. However, TIIA did not show statistically significant effects. In addition, there were no statistically significant differences in pairwise comparisons between the five herbal monomers (Table 1, Fig. 5).Table 1 Network meta-analysis results of rat arterial balloon injury model.

Table 1GS						
0.17 (−0.39,0.72)	ASIV					
−0.40 (−1.06,0.26)	0.57 (−1.35,0.21)	TIIA				
−0.32 (−1.00,0.36)	−0.48 (−1.28,0.32)	0.09 (−0.79,0.96)	TMP			
0.36 (−0.25,0.98)	0.20 (−0.54,0.94)	0.76 (−0.06,1.59)	0.68 (−0.16,1.52)	TPNS		
−0.99 (-1.25,-0.73)	−1.16 (-1.65,-0.67)	−0.59 (−1.20,0.02)	−0.68 (-1.31,-0.05)	−1.36 (-1.91,-0.80)	Placebo	
Bold values are significant pairwise comparisons.

Fig. 5 Forest plot for the network meta-analysis.

Fig. 5

Using the surface under the cumulative ranking (SUCRA) method to rank the superiority and inferiority of different intervention drugs, the size of the area under the curve was used to evaluate the likelihood of the five herbal monomers being the most effective intervention measures. The results showed that TPNS was the most effective herbal monomer in reducing intimal hyperproliferation in rats with carotid artery balloon injury and lowering the I/M ratio, as illustrated in Fig. 6(A and B).Fig. 6 Probability ranking curve. The vertical axis represents probability or cumulative probability, while the horizontal axis represents ranks. (A) Probability ranking curve; (B) Cumulative probability ranking curve.

Fig. 6

The initial vascular response after balloon injury includes vascular recoil, platelet thrombi and thrombus formation, platelet and fibrin deposition, and adhesion of circulating neutrophils and monocytes. Neointimal hyperproliferation is also a reparative process stimulated by various coagulation and inflammatory factors promoting VSMC proliferation and ECM formation. Platelet- and leukocyte-derived growth factors further stimulate VSMC proliferation, accelerating ECM formation and promoting migration to the nascent neointima. Simultaneously, incomplete endothelial regeneration leads to excessive lipid uptake and accelerated development of atherosclerotic plaques [16]. TPNS can inhibit nuclear factor kappa-B (NF-κB) DNA binding activity [17] and reduce the expression of pro-inflammatory factors vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) [18], thereby reducing the recruitment of monocytes by chemokines and surface adhesion molecules on endothelial cells. This exerts an inhibitory effect on neointimal hyperproliferation during acute inflammatory response. Additionally, TPNS can inhibit VSMC proliferation and induce apoptosis by upregulating tumor protein p53 (p53), Bcl-2-associated X protein (Bax), caspase-3 and downregulating B-cell lymphoma-2 (Bcl-2) [19]. TPNS can promote re-endothelialization by mobilizing endothelial progenitor cells, exerting an inhibitory effect on excessive VSMC proliferation [20].

ASIV inhibits the toll-like receptor 4 (TLR4)/NF-κB pathway, thereby reducing the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which in turn decreases the expression of VCAM-1, ICAM-1, TLR4, and nuclear NF-κB p65. This increases nitric oxide (NO) production and endothelial NO synthase (eNOS) expression, improving endothelial dysfunction [21]. Moreover, ASIV can activate the cellular viability of endothelial cells and smooth muscle cells, promoting extracellular matrix secretion, which may lead to excessive VSMC proliferation after balloon injury. However, ASIV can still inhibit VSMC proliferation and migration by suppressing the p38 mitogen-activated protein kinase (MAPK) signaling pathway [22], which may be one of the reasons for its lower ranking.

GS can exert its inhibitory effects on VSMC proliferation, migration, calcification, and apoptosis induction through the phospoinositide 3-kinases (PI3K)/protein kinase B (Akt) pathway, inhibiting the activation of NF-κB and MAPKs, alleviating inflammation [23]. Moreover, GS can also inhibit monocyte adhesion and foam cell formation, thereby reducing neointimal formation [24].

TMP reduces the levels of MCP-1 and ICAM-1, thereby reducing neointimal formation and reactive oxygen species (ROS) production, blocking the anti-inflammatory effect of the NF-κB pathway [25]. Additionally, TMP can inhibit adenosine diphosphate-induced platelet aggregation and thromboxane A2 secretion, exerting an antiplatelet effect [26].

TIIA inhibits the MAPK signaling pathway to restrain VSMC proliferation and migration [27]. Additionally, TIIA may exert anti-proliferative effects by activating the adenosine monophosphate-activated protein kinase (AMPK)–p53–cyclin-dependent kinase inhibitor 1 (p21) signaling pathway and anti-migratory effects by inhibiting AMPK/NF-κB [28]. In summary, the five TCM monomers compared in this study exert varying degrees of inhibition on neointimal hyperproliferation in the balloon injury model. However, due to the different balloon models and injury energies used in each study, the degree of injury to the animal models may vary, which may be a key reason for the differences in efficacy rankings. Furthermore, the different administration routes and drug purity can also impact the rankings.

3.4.1.3 Publication bias

Most studies are symmetrically distributed on both sides of the comparison-adjusted funnel plot, suggesting a lower likelihood of publication bias, as shown in Fig. 7. Similarly, the Egger test (P = 0.0878) indicated no publication bias.Fig. 7 The comparison-correction funnel plot.

Fig. 7

3.4.2 Rabbit arterial balloon injury model

3.4.2.1 Network evidence map

A total of 6 studies were included in the NMA, including 3 studies on TMP, 2 on TIIA, and 1 on TPNS (Fig. 8).Fig. 8 Evidence network diagram of rabbit arterial balloon injury model.

Fig. 8

3.4.2.2 NMA results

A total of 6 studies reported the efficacy of different herbal monomers in reducing intimal hyperproliferation in rabbits with arterial balloon injury (TMP vs Placebo (n = 3), TIIA vs Placebo (n = 2), TPNS vs Placebo (n = 1)). The results showed that the following results: TMP vs Placebo (SMD: 0.37, 95%CI: 0.81 to 0.08), TIIA vs Placebo (SMD: 0.36, 95%CI: 0.87 to 0.15), TPNS vs Placebo (SMD: 1.23, 95%CI: 1.97 to −0.49). Compared to the control group, herbal monomers TMP, TIIA, and TPNS were effective in reducing postoperative intimal hyperproliferation and lower the I/M ratio (Table 2, Fig. 9). The ranking results indicated that TPNS might be the most effective herbal monomer in reducing intimal hyperproliferation in rabbits with carotid artery balloon injury and lowering the I/M ratio, as illustrated in Fig. 10(A and B).Table 2 Network meta-analysis results of rabbit arterial balloon injury model.

Table 2TMP				
−0.01 (−0.69,0.67)	TIIA			
0.86 (0.00,1.72)	0.87 (−0.03,1.77)	TPNS		
−0.37 (−0.81,0.08)	−0.36 (−0.87,0.15)	−1.23 (-1.97,-0.49)	Placebo	
Bold values are significant pairwise comparisons.

Fig. 9 Forest plot for the network meta-analysis.

Fig. 9

Fig. 10 Probability ranking curve. The vertical axis represents probability or cumulative probability, while the horizontal axis represents ranks. (A) Probability ranking curve; (B) Cumulative probability ranking curve.

Fig. 10

Due to the limited number of studies on herbal monomer interventions in the rabbit arterial balloon injury model and the insufficient sample size, TMP and TIIA did not show statistical significance. However, TMP and TIIA exhibited strong potential as herbal monomers in reducing intimal hyperproliferation. The single study on TPNS included in this NMA leads to insufficient reliability of the results. Therefore, more related studies are required in the future to support our findings.

4 Discussion

Being the first study to evaluate the efficacy of herbal monomers in reducing intimal hyperproliferation in arterial balloon injury models, this meta-analysis collated relevant original studies as comprehensively as possible. However, due to differences in experimental design, implementation standards, and outcome reporting, a comprehensive and scientific evaluation is required. Separate NMAs were conducted for studies involving rats and rabbits. For the rat model, compared to the negative control group, the TCM monomers GS, ASIV, TMP, and TPNS could effectively reduce postoperative intimal hyperproliferation and lower I/M ratio, whereas TIIA did not exhibit statistically significant effects, possibly due to the limited number of included studies and insufficient sample size. Additionally, the results of rank ordering and SUCRA values suggested that TPNS was the most effective TCM monomer in reducing intimal hyperproliferation in rats with arterial balloon injury and lowering the I/M ratio, followed by ASIV and GS. For the rabbit model, compared to the control group, the TCM monomers TPNS, TMP, and TIIA reduced postoperative neointimal hyperproliferation and decreased the I/M ratio. SUCRA results indicated that, compared to TIIA and TMP, TPNS was the most effective TCM monomer in reducing neointimal hyperproliferation and decreasing the I/M ratio in rabbits with arterial balloon injury. In summary, the limited sample size of the studies included necessitates further research with larger sample sizes to validate the present study's findings.

During PCI, irreversible damage is inflicted on the vascular endothelium, resulting in poor intercellular connections, reduced expression of anti-thrombotic molecules, and decreased production of vasodilators [29]. Impaired endothelial cell barrier function leads to rapid deposition of platelets and fibrinogen at the injury site, initiating thrombus formation [30]. Following the initial vascular response, the ongoing inflammatory reaction at the injury site recruits monocytes and neutrophils from the circulation. Under the direct or indirect stimulation of various cytokines, normal VSMC in the medial layer transitions from a contractile state to a highly proliferative and migratory phenotype, migrating to the intima and accelerating the aggregation of ECM, which leads to intimal thickening and gradually causes vascular lumen narrowing [31]. However, Restenosis is directly related to the recurrence of angina or acute coronary syndrome and may lead to target lesion revascularization (coronary artery bypass grafting or repeat PCI), severely affecting the patient's quality of life and long-term prognosis [32]. Additionally, restenosis is an independent predictor of mortality during follow-up [33]. Therefore, the I/M ratio is the most direct indicator of restenosis and is used as a primary outcome measure.

This meta-analysis demonstrates TPNS to be the most effective among the five TCM monomers in reducing neointimal hyperproliferation in both rat and rabbit models of arterial balloon injury. As the most important active component of Panax notoginseng, TPNS has attracted widespread attention in its application in cardiovascular diseases, which is due to its anti-inflammatory, anti-apoptotic, anti-hypoxic, lipid-lowering, anti-coagulant, and anti-atherosclerotic properties. The phenotypic transformation of VSMC is closely related to the MAPK pathway [34] and Akt signaling transduction [35]. The Akt pathway maintains the contractile phenotype of VSMCs [36], whereas the activation of the MAPK pathway induces cell proliferation [37]. TPNS inhibits the aggregation of VSMC myosin through the PI3K/Akt signaling pathway, thereby exerting an inhibitory effect on VSMC proliferation and migration [23]. It can also protect against neointimal hyperproliferation by inhibiting the extracellular regulated kinase (ERK)/MAPK signaling pathway [38]. Additionally, TPNS can inhibit the vitality, proliferation, and migration of VSMCs by promoting the expression of Wilms tumor 1 (WT1)-related proteins [39]. Therefore, TPNS may exert its inhibitory effect on intimal hyperproliferation after rat carotid artery balloon injury through multiple pathways. Inflammation is a continuous process throughout the repair of vascular injury. Besides inhibiting the activation of the NF-κB pathway, TPNS can increase the activity of superoxide dismutase (SOD), reduce the release of inflammatory factors such as malondialdehyde and IL-6, weaken inflammatory damage, and inhibit the formation of neointima [40]. TPNS has been found to exert an anti-atherosclerotic effect. Studies have found that TPNS can reduce the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), IL-6, and C-reactive protein by inhibiting phosphorylation of focal adhesion kinase, expression of integrin, and translocation of NF-κB and significantly increasing the level of high-density lipoprotein cholesterol [41]. TPNS is involved in various pathological stages after balloon injury in the model and exerts anti-inflammatory and anti-proliferative effects on VSMC proliferation and migration through multiple pathways. It can also accelerate re-endothelialization to improve vascular endothelial function, jointly exerting an inhibitory effect on neointimal hyperproliferation. However, the limited number of studies related to TPNS included in this meta-analysis necessitates more relevant research to support the present study's conclusions.

ASIV is another promising TCM monomer that reduces intimal hyperproliferation in arterial balloon injury models. Previous studies have confirmed that ASIV exhibits various pharmacological effects, including anti-inflammatory, anti-fibrotic, anti-oxidative stress, and cardioprotective effects. The loss of vascular endothelium integrity is crucial in the pathogenesis of restenosis. ASIV can reduce ROS levels, increase NO production and expression of eNOS, enhance SOD activity, alleviate vascular endothelial dysfunction, promote endothelial injury repair, and restore the barrier function of endothelial cells [42,43]. Furthermore, ASIV can reduce the production of ROS, increase the activity of SOD, help cells resist oxidative stress damage, regulate mitochondrial energy metabolism and ion homeostasis [44], and exert protective effects by inhibiting the TLR4/NF-κB pathway to reduce the increased levels of inflammatory factors such as IL-6 and TNF-α resulting from acute inflammatory reactions after PCI [21]. ASIV can activate the PI3K/Akt/mTOR pathway to inhibit VSMC autophagy, thereby suppressing intimal hyperproliferation [45]. In the balloon injury model, ASIV mainly improves endothelial function, promotes endothelial injury repair, and exerts anti-inflammatory effects, thereby reducing neointimal hyperproliferation. Therefore, ASIV holds immense potential for treating restenosis, necessitating further research.

The other TCM monomers (GS, TMP, and TIIA) are also indispensable in the treating restenosis after PCI. Currently, the various subtypes of GS discovered include Rb3, Rh1, Rg1, etc. Previous studies have found that ginsenosides inhibit the proliferation and migration of VSMCs through different mechanisms. For example, in the angiotensin II (Ang II) injury model, GS Rb3 inhibits VSMC proliferation by blocking the cell cycle [46]. GS Rh1 inhibits VSMC migration and proliferation by suppressing the ROS-mediated ERK signaling pathway [47]. Under the stimulation of platelet-derived growth factor BB (PDGF-BB), GS Rg1 inhibits the TNF-α-activated protein kinase C (PKC) pathway, increases the formation of NO, and plays a role in inhibiting VSMC proliferation [48]. Similarly, the intestinal metabolite of GS, compound K, can reduce PDGF-BB-stimulated VSMC proliferation and migration by blocking the cell cycle [49]. GS can also reduce the production of inflammatory factors such as ICAM-1, VCAM-1, TNF-α, and IL-6 by inhibiting the NF-κB pathway. The current research on GS targets different subtypes. However, in this study, the effects of GS were analyzed uniformly, neglecting the heterogeneity between different subtypes to some extent, which may make the conclusions more conservative.

The anti-atherosclerotic effect of TMP may be related to regulating intracellular cholesterol efflux, inhibiting ROS, SOD, and catalase activity, as well as regulating the peroxisome proliferator-activated receptor gamma/liver X receptor alpha/adenosine triphosphate-binding cassette transporter 1 pathway [50]. TMP reduces LDL oxidation and inhibits the transformation of macrophages into foam cells and the deposition and migration of VSMCs and collagen by regulating multiple signaling pathways [26]. TMP can also alleviate inflammation by blocking extracellular signal-regulated kinase, p38 MAPK, and NF-κB signaling pathways to reduce the expression of IL-8 [51]. In the Ang II injury model, TMP increases NO production, dilates blood vessels, and inhibits calcium/calmodulin-dependent protein kinase activity to help inhibit VSMC proliferation and migration [52]. Altogether, TMP can reduce LDL oxidation, decrease inflammation, inhibit smooth muscle cell migration, and suppress platelet activation. These outcomes are crucial for reducing the occurrence of restenosis.

Although the efficacy of TIIA was not statistically different in this analysis, its therapeutic effect on restenosis cannot be neglected. TIIA can reduce the expression and membrane translocation of chloride intracellular channel 1 to decrease the levels of TNF-α, IL-6, VCAM-1, and other inflammatory factors in atherosclerotic mice [53]. TIIA has a protective effect on endothelial cells, weakening the inflammatory damage to the endothelium by inhibiting the upregulation of pro-inflammatory factors [54] and regulating vascular tension by increasing the release of vasodilators [55]. TIIA inhibits endothelial cell apoptosis through the PI3K/Akt/eNOS signaling pathway [56]. Additionally, TIIA can suppress VSMC proliferation and migration through AMPK activation [27]. It can also reduce the levels of chemotactic factors such as IL-8 and MCP-1 and decrease the ratio of the apoptotic factors Bax to Bcl-2 to inhibit neointimal hyperproliferation. In summary, TIIA's action mechanism includes inhibiting low-density lipoprotein oxidation, proliferation, and migration of smooth muscle cells, adhesion of monocytes to arterial endothelium, expression of pro-inflammatory cytokines, and platelet aggregation to suppress neointimal proliferation. Although GS, TMP, and TIIA ranked relatively low in efficacy in this study, their inhibitory effects on neointimal proliferation in the balloon injury model cannot be overlooked. The diverse effects of different Chinese herbal monomers through different pathways demonstrate their multi-targeted approach.

In recent years, TCM has attracted researchers' attention due to its multi-pathway, multi-target effects. Compared to TCM as a whole, TCM monomers offer advantages such as distinct composition, higher pharmacological activity, and controllable bioavailability. In post-PCI patients, the hyperproliferation of the intimal layer leads to late lumen loss, resulting in restenosis, which severely affects the patient's quality of life and long-term prognosis. Our study found that TCM monomers can effectively reduce intimal hyperproliferation in arterial balloon injury models, lowering the I/M ratio, providing animal experimental evidence for the clinical application of TCM monomers. In addition, the combined use of multiple drug monomers may increase the efficacy in reducing the occurrence of restenosis.

5 Limitations

The present study poses some limitations. (1) Despite the efforts to expand the search scope and collect as many relevant studies on the five Chinese herbal monomers as possible, the number of studies included in this research remains limited, and the sample size is inadequate, which may affect the precision of the conclusions. (2) Due to the inclusion of only SD rats and New Zealand rabbits in this study, and all studies were conducted in China, the generalizability of our results to other species and regions may be limited. (3) The I/M ratio was considered the sole outcome indicator because it is the most intuitive manifestation of restenosis. However, due to the lack of uniform reporting and insufficient reports on other indicators, this study was unable to focus on other outcome indicators. (4) This study only chose five common TCM monomers used for treating restenosis after PCI; however, this does not indicate that other TCM monomers do not have potential therapeutic effects. (5) The purity and administration routes of various TCM monomers may introduce heterogeneity. However, due to the limited number of studies included, this NMA adopted a random-effects model for analysis, the conclusions of which may lean toward conservatism.

Therefore, in the future, more large-sample mechanistic studies of traditional Chinese medicine monomers should be conducted across multiple regions and verified in various species of experimental animals. Standardizing animal research procedures and unifying experimental result reporting standards are essential. Additionally, more large-sample, multicenter randomized controlled trials of traditional Chinese medicine monomers should be conducted to provide higher quality clinical and preclinical evidence for reducing post-PCI restenosis.

6 Conclusion

The NMA results suggest that TCM monomers can effectively reduce hyperproliferation in arterial balloon injury models, lowering the I/M ratio. TPNS was the most effective TCM monomer among the five studied. However, the research on TIIA is insufficient, and the limited sample size may affect the robustness of the results. In addition, most research on TCM monomers is currently at the experimental stage, lacking clinical validation. Conducting standardized animal experiments and reporting their findings can improve the quality of evidence from animal experiments, providing a foundation for future clinical trials.

Funding

This study was supported by the 10.13039/501100001809 National Natural Science Foundation of the People's Republic of China (No. 8207142519 ).

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Data included in article/supp. material/referenced in article.

Ethics declarations

Review and/or approval by an ethics committee was not needed for this study because [This work is a review of the literature and does not address the ethical considerations of animal, cell, and human experimentation.].

CRediT authorship contribution statement

Long Xie: Writing – review & editing, Writing – original draft, Data curation. Tianshi Mao: Data curation. Qun Gao: Data curation. Yi Pan: Methodology. Zhifei Yang: Software. Xinyan Qu: Validation. Ruli Feng: Validation. Junyan Xia: Validation. Qian Lin: Supervision. Jie Wan: Funding acquisition.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jie Wan reports financial support was provided by 10.13039/501100001809 National Natural Science Foundation of China . If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviation

PCI Percutaneous coronary intervention

MACE major adverse cardiovascular events

VSMC vascular smooth muscle cell

ECM extracellular matrix

CCA common carotid artery

TCM Traditional Chinese Medicine

GS ginsenoside

ASIV astragaloside IV

TIIA tanshinone IIA

TMP ligustrazine

TPNS total panax notoginsenoside

NMA network meta-analysis

I/M intima-to-media

SD Sprague-Dawley

SYRCLE SYstematic Review Centre for Laboratory Animal Experimentation

SMD standardized mean difference

CI confidence interval

SUCRA Surface Under the Cumulative Ranking

NF-κB nuclear factor kappa-B

VCAM-1 vascular cell adhesion molecule-1

ICAM-1 intercellular adhesion molecule-1

MCP-1 monocyte chemoattractant protein-1

p53 tumor protein p53

Bax Bcl-2-associated X protein

Bcl-2 B-cell lymphoma-2

IL-6 interleukin-6

TNF-α tumor necrosis factor-α

TLR4 toll-like receptor 4

NO nitric oxide

eNOS endothelial NO synthase

MAPK mitogen-activated protein kinase

PI3K phospoinositide 3-kinases

Akt protein kinase B

ROS reactive oxygen species

AMPK adenosine monophosphate-activated protein kinase

p21 cyclin-dependent kinase inhibitor 1

ERK extracellular regulated kinase

WT1 Wilms tumor 1

SOD superoxide

LDL-C low-density lipoprotein cholesterol

Ang II angiotensin II

PDGF-BB platelet-derived growth factor BB

PKC TNF-α-activated protein kinase C

Appendix A Supplementary data

The following are the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Multimedia component 2

Multimedia component 2

Multimedia component 3

Multimedia component 3

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36327.
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