Integrating Network Pharmacology and Experimental Verification to Explore the Targets and Mechanism for Panax Notoginseng Saponins against Coronary In-stent Restenosis.

BACKGROUND: Despite widespread application of drug-eluting stents in coronary intervention, in-stent restenosis (ISR) is still a daunting complication in clinical practice. Panax notoginseng saponins (PNS) are considered to be effective herb compounds for preventing ISR. OBJECTIVE: This study aimed to elucidate the targets and mechanisms of PNS in ISR prevention using network pharmacology approaches and experimental verification. METHODS: Relevant targets of PNS active compounds were collected from the HERB database and PharmMapper. The ISR-related targets were obtained from the GeneCards database and the Comparative Toxicogenomics Database. The GO and KEGG enrichment analysis was performed using R software. The String database and Cytoscape software were employed to build the PPI and compounds-targets-pathways-disease networks. Finally, Molecular docking performed by Autodock Vina and cellular experiments were used to validate network pharmacology results. RESULTS: There were 40 common targets between PNS targets and ISR targets. GO analysis revealed that these targets focused on multiple ISR-related biological processes, including cell proliferation and migration, cell adhesion, inflammatory response, and anti-thrombosis and so on. The KEGG enrichment results suggested that PNS could regulate multiple signaling pathways to inhibit or delay the development and occurrence of ISR. The molecular docking and cellular experiments results verified the network pharmacology results. CONCLUSION: This study demonstrated that the potential molecular mechanisms of PNS for ISR prevention involved multiple compounds, targets, and pathways. These findings provide a theoretical reference and experimental basis for the clinical application and product development of PNS for the prevention of ISR.

Risk factors for in-stent restenosis after coronary stent implantation in patients with coronary artery disease: A retrospective observational study.

To explore the risk factors for in-stent restenosis (ISR) after stent implantation in patients with coronary heart disease (CHD) using logistic regression analysis. From February 2020 to February 2022, 350 patients with CHD after percutaneous coronary intervention (PCI) were divided into a stent stenosis group and a stent nonstenosis group based on coronary angiography results performed 2 years after PCI. Univariate and multivariate logistic regressions were used to analyze the factors related to ISR after coronary stent implantation in patients with CHD. This study was approved by the Ethics Committee of Shandong University of Traditional Chinese Medicine. Patient signed informed consent. Of the 350 patients with CHD, 138 (39.43%) had stent restenosis while 212 did not. Univariate analysis showed that a family history of CHD, history of type 2 diabetes, hypertension, smoking, and drinking, discontinuation of aspirin, use of conventional dose statins, calcified lesions, ≥ 3 implanted stents, stent length ≥ 30 mm, stent diameter < 3 mm, and tandem stent increased the risk of restenosis. The incidence of restenosis was higher in the stent group than that in the nonstent group (P < .05). There were no significant differences in the blood lipid level, left ventricular ejection fraction, clopidogrel/ticagrelor or beta-blocker withdrawal, location of culprit vessels, and thrombotic lesions between the 2 groups (P > .05). Multivariate logistic regression analysis showed that family history of CHD, history of type 2 diabetes, hypertension, smoking, and drinking, aspirin withdrawal, use of conventional doses of statins, calcified lesions, ≥ 3 implanted stents, stent length ≥ 30 mm, stent diameter < 3 mm, and tandem stenting were risk factors for ISR within 2 years after PCI. A family history of CHD, history of type 2 diabetes, hypertension, smoking, and drinking, discontinuation of aspirin, use of conventional dose statins, calcified lesions, ≥ 3 stent implantations, stent length ≥ 30 mm, stent diameter < 3 mm, and tandem stenting are risk factors for ISR within 2 years after PCI in patients with CHD.

Euonymine inhibits in-stent restenosis through enhancing contractile phenotype of vascular smooth muscle cells via modulating the PTEN/AKT/mTOR signaling pathway.

BACKGROUND: Percutaneous coronary intervention (PCI) is an effective treatment for acute myocardial infarction, but the postoperative in-stent re-stenosis (ISR) remains a major risk factor that affects the prognosis of PCI. Clinically, drug-eluting stents (DES) are widely applied to prevent and treat ISR. However, only a few stent coating drugs are currently available for clinical use, including paclitaxel and rapamycin (sirolimus) and their derivatives. These stent-coated drugs have led to a decrease in restenosis rates, but the major adverse outcomes, such as delayed endothelial healing and increased in-stent thrombosis, seriously reduce their therapeutic effects. PURPOSE: Herein, we explored the potential efficacy of Euonymine (Euo), an alkaloid extracted from Tripterygium Hypoglaucum (Levl) Hutch (THH, Lei gong Teng), for the prevention against ISR after PCI. STUDY DESIGN: Our study depicts the potential efficacy of Euo in treating ISR and explores its mechanism with in vitro and in vivo models. METHODS: Primary vascular smooth muscle cells (VSMCs) from the rabbit thoracic aorta were cultured, and the proliferation and migration of VSMCs were monitored. Apoptosis was measured by Transmission Electron Microscopy and TUNEL staining assay. Protein and gene levels were measured to explore the underlying molecular mechanisms. In vivo models of porcine coronary implantation and rabbit carotid balloon injury are used to validate the efficacy of Euo in inhibiting ISR after PCI. RESULTS: With an ox-LDL-injured cell model, we showed that Euo suppressed the proliferation and migration of the rabbit thoracic aorta primary VSMCs, while inducing their apoptosis. We next established a rabbit carotid balloon injury model in which the phosphorylation levels of PI3K and AKT1 (Ser473) as well as mTOR activity were significantly elevated compared to the sham-operated control. These activities were significantly attenuated by the Euo intervention. Additionally, the balloon angioplasty significantly increased the expression of Bcl-2, while decreased the expression of Bax and caspase-3. Euo intervention significantly increased the ratio of Bax/Bcl-2 and the level of caspase-3. Taken together, Euo may enhance the VSMCs contractile phenotype by modulating the PTEN/AKT/mTOR signaling pathway. Furthermore, with two in vivo models, the porcine coronary artery implantation model, and the rabbit carotid balloon injury model, we demonstrated that Euo-eluting stents indeed inhibited ISR after PCI. CONCLUSION: For the first time, this study delineates the potential efficacy of Euo, derived from Tripterygium Hypoglaucum (Levl) Hutch, in ameliorating ISR after PCI with two in vivo models. The phytochemical targets PTEN/AKT/mTOR signaling pathway to increase the contractile phenotype of VSMCs and exerts anti-proliferative, anti-migratory as well as pro-apoptotic effects, thereby inhibiting the ISR.

Cardiotonic Pills® protects from myocardial fibrosis caused by in stent restenosis in miniature pigs.

BACKGROUND: Stent implantation has been increasingly applied for the treatment of obstructive coronary artery disease, which, albeit effective, often harasses patients by in-stent restenosis (ISR). PURPOSE: The present study was to explore the role of compound Chinese medicine Cardiotonic Pills® (CP) in attenuating ISR-evoked myocardial injury and fibrosis. STUDY DESIGN: Chinese miniature pigs were used to establish ISR model by implanting obsolete degradable stents into coronary arteries. Quantitative coronary angiography (QCA) was performed to confirm the success of the model. METHODS: CP was given at 0.2 g/kg daily for 30 days after ISR. On day 30 and 60 after stent implantation, the myocardial infarct and myocardial blood flow (MBF) were assessed. Myocardial histology was evaluated by hematoxylin-eosin and Masson's trichrome staining. The content of ATP, MPO, and the activity of mitochondrial respiratory chain complex Ⅳ were determined by ELISA. Western blot was performed to assess the expression of ATP5D and related signaling proteins, and the mediators of myocardial fibrosis. RESULTS: Treatment with CP diminished myocardial infarct size, retained myocardium structure, attenuated myocardial fibrosis, and restored MBF. CP ameliorated energy metabolism disorder, attenuated TGFß1 up-regulation and reversed its downstream gene expression, such as Smad6 and Smad7, and inhibited the increased expression of MCP-1, PR S19, MMP-2 and MMP-9. CONCLUSION: CP effectively protects myocardial structure and function from ISR challenge, possibly by regulating energy metabolism via inactivation of RhoA/ROCK signaling pathway and inhibition of monocyte chemotaxis and TGF ß1/Smads signaling pathway.

[Advances in risk prediction model of disease and syndrome combination and concept of construction of risk prediction model for in-stent restenosis after PCI].

Traditional Chinese medicine(TCM) has its unique understanding of the etiology, pathogenesis, and risk factors of di-seases, and is advantageous in the study of risk prognosis.First recorded in Huangdi's Internal Classic, the TCM theory of treating di-sease before its onset has a long history.Supplemented and improved by the later generations of doctors, the TCM theory of treating di-sease before its onset has been applied to clinical practice and achieved good results.With the development of modern medicine, it has become a new trend to construct the risk prediction model integrating the research results of modern medicine with disease and syndrome combination of TCM characteristics.The construction of risk prediction model of disease and syndrome combination is conducive to early clinical screening and intervention, and provides ideas for the integration of TCM and western medicine.Coronary heart disease(CHD) is one of the common chronic diseases, and percutaneous coronary intervention(PCI) is an important therapeutic approach.In-stent restenosis(ISR) is a common complication after PCI, which seriously affects the outcome and prognosis of patients.Although some patients can be treated with balloon dilatation and endovascular stents, a significant number of patients still refuse secondary stenting intervention.The construction of risk prediction model of disease and syndrome combination for ISR after PCI can provide an effective tool for clinical risk prediction of ISR and indicators with TCM characteristics for early screening and intervention of people at a high risk of ISR, and guide clinical monitoring and intervention, which has certain clinical significance and reference value for the prevention and reduction of ISR.

Association between Green Tea Consumption and In-Stent Restenosis in a Chinese Population after Percutaneous Coronary Intervention.

In spite of the remarkable advances in novel drug and revascularization procedure, in-stent restenosis (ISR) remains a major complication of percutaneous coronary intervention (PCI). The aim of this study was to investigate the association between green tea consumption and the incidence of ISR. The study population consisted of 1,509 patients who underwent PCI with drug-eluting stent (DES) implantation from January 2017 to December 2019. Patients were divided into ISR and non-ISR group according to the results of coronary angiography reexamination about 1 y after PCI. Multivariate logistic regression analysis was used to determine the relationship between green tea consumption and the risk of ISR. ISR occurred in 157/1,509 patients (10.4%) by follow-up coronary angiography. After adjusting for other confounding factors, green tea consumption was associated with a reduced risk of ISR (OR 0.653, 95%CI 0.460-0.926, p=0.017). The risk of ISR tended to decline with an increase in the quantity of green tea consumed (adjusted p for trend=0.006). The adjusted ORs for those consuming 125-249 g and ≥250 g of dried green tea leaves per month were 0.579 (95%CI, 0.346-0.970, p=0.038) and 0.501 (95%CI, 0.270-0.932, p=0.029), respectively, compared with non-tea drinkers. Moreover, significant dose-response relationships were also observed for both frequency (adjusted p for trend=0.011) and concentration (adjusted p for trend=0.004) of green tea intake on the risk of ISR. Green tea consumption can protect against the development of ISR in a Chinese population.

The effectiveness of Salvianolate injection for in-stent restenosis after percutaneous coronary intervention: A protocol for systematic review and meta-analysis.

BACKGROUND: In-stent restenosis (ISR) caused by vascular remodeling after percutaneous coronary intervention limits the long-term efficacy of this method. Salvianolate injection is now widely used in the clinical treatment of ISR. However, there is no systematic review or meta-analysis to evaluate the effects of Salvianolate injection on ISR. METHODS: We will search articles in 8 electronic databases, including the Cochrane Central Register of Controlled Trials, PubMed, Embase, the Web of Science, China National Knowledge Infrastructure, the Chinese Biomedical Literature Database, Wanfang Database, and the Chinese Scientific Journal Database for randomized controlled trials of ISR treated by Salvianolate injection from their inception to February 27, 2022. The primary outcome measure will be the restenosis rate. The data meeting the inclusion criteria were analyzed by RevMan V.5.4 software. Two authors evaluated the study using the Cochrane collaborative risk bias tool. We will use a scoring method to assess the overall evidence supporting the main results. RESULTS: This study will analyze the clinical effectiveness of Salvianolate injection in the treatment of ISR. CONCLUSION: The findings of this systematic review will provide evidence to evaluate the effectiveness of Salvianolate injection for the treatment of ISR. INPLASY REGISTRATION NUMBER: INPLASY202220117.

The effect of Huoxue Huayu decoction on restenosis after percutaneous coronary intervention in patients with coronary heart disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Percutaneous coronary intervention (PCI), as the most common treatment for coronary heart disease (CHD), has the advantages of simple operation, minimal invasion, rapid reconstruction, and vessels opening. The problem, however, is that many patients develop restenosis within 6 months after PCI. In traditional Chinese medicine (TCM), Huoxue Huayu decoction (HXHYD) is widely used to treat cardiovascular diseases, and its important role as a complementary and alternative therapy for the prevention and treatment of post-PCI restenosis in CHD patients has been extensively reported. However, controversy exists among different studies. Therefore, we collected relevant randomized controlled trials for a meta-analysis to assess the efficacy and safety of HXHYD in the prevention of post-PCI restenosis in patients with CHD. METHODS: Randomized controlled trials of HXHYD in the prevention of post-PCI restenosis in patients with CHD will be retrieved from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wan Fang Database, Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, and Clinical Trial Register. The 2 authors will independently conduct the literature search, literature screening, data extraction, and quality assessment. Data analysis will be performed using STATA 14.0. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will provide high-quality, evidence-based medical evidence for the efficacy and safety of HXHYD in the prevention of post-PCI restenosis in patients with CHD. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms. This review would be disseminated in a peer-reviewed journal or conference presentations. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/PNZSM.

Preclinical Evaluation of a Novel Polymer-free Everolimus-eluting Stent in a Mid-term Porcine Coronary Restenosis Model.

BACKGROUND: Titanium dioxide films exhibit good biocompatibility and may be effective as drug-binding matrices for drug-eluting stents. We conducted a mid-term evaluation of a novel polymer-free everolimus-eluting stent using nitrogen-doped titanium dioxide film deposition (TIGEREVOLUTION®) in comparison with a commercial durable polymer everolimus-eluting stent (XIENCE Alpine®) in a porcine coronary restenosis model. METHODS: Twenty-eight coronary arteries from 14 mini-pigs were randomly allocated to TIGEREVOLUTION® stent and XIENCE Alpine® stent groups. The stents were implanted in the coronary artery at a 1.1-1.2:1 stent-to-artery ratio. Eleven stented coronary arteries in each group were finally analyzed using coronary angiography, optical coherence tomography, and histopathologic evaluation 6 months after stenting. RESULTS: Quantitative coronary analysis showed no significant differences in the pre-procedural, post-procedural, and 6-month lumen diameters between the groups. In the volumetric analysis of optical coherence tomography at 6 months, no significant differences were observed in stent volume, lumen volume, and percent area stenosis between the groups. There were no significant differences in injury score, inflammation score, or fibrin score between the groups, although the fibrin score was zero in the TIGEREVOLUTION® stent group (0 vs. 0.07 ± 0.11, P = 0.180). CONCLUSION: Preclinical evaluation, including optical coherence tomographic findings 6 months after stenting, demonstrated that the TIGEREVOLUTION® stent exhibited efficacy and safety comparable with the XIENCE Alpine® stent, supporting the need for further clinical studies on the TIGEREVOLUTION® stent.

Effect of Tongguan Capsules () on Restenosis after Coronary Stent Implantation: Study Protocol for A Randomized Controlled Trial.

BACKGROUND: Although percutaneous coronary intervention (PCI) had become widely employed therapeutic procedure for coronary artery disease, stent restenosis limited the benefits of this revascularization and the question how to prevent such events remained unresolved. While numerous empirical observations suggested Tongguan Capsules (), a patented Chinese Medicine, could decrease frequency and duration of angina pectoris attacks, evidence supporting its efficacy on restenosis remained inadequate. OBJECTIVE: This trial was designed to determine whether Tongguan Capsules would reduce restenosis rate in patients after successful stent implantation. METHODS: Approximately 400 patients undergoing percutaneous coronary stent deployment were enrolled and randomized to control group or Tongguan Capsules (4.5 g/d) for 3 months. All patients received standard anti-platelet, anti-coagulation and lipid-decreasing treatments, concurrently. The primary clinical endpoint was the 12-month incidence of the major adverse cardiovascular events (defined as cardiac death, myocardial infarction, and recurrence of symptoms requiring additional revascularization). The angiographic end point was restenosis rate at 6 months. CONCLUSION: This study would provide important evidence for the use of Tongguan Capsules in patients after stent implantation in combination with routine therapies, which may significantly reduce incidence of the restenosis so as to potentially improve the clinical outcomes. (registration number: ChiCTR-TRC- ChiCTR-IIR-17011407).

A randomized comparison of a novel iopromide-based paclitaxel-coated balloon Shenqi versus SeQuent Please for the treatment of in-stent restenosis.

BACKGROUND: Treatment of coronary in-stent restenosis (ISR) remains challenging in contemporary clinical applications. Drug-coated balloon (DCB) angioplasty offers an effective treatment for ISR. Shenqi is a novel iopromide-based paclitaxel-coated balloon and its clinical safety, effectiveness and angiographic efficacy in patients with ISR have not been investigated. METHODS: A total of 216 subjects with the first occurrence of ISR at 11 investigational sites in China were randomly allocated in a 1:1 fashion to treatment with DCB SeQuent Please or Shenqi. Clinical follow-up was planned at 1, 6, 9 and 12 months, and angiographic follow-up was planned at 9 months. The study was powered for the primary endpoint of 9-month in-segment late loss. RESULTS: At 9-month follow-up, the in-segment late loss was 0.29 ± 0.43 mm with Shenqi versus 0.30 ± 0.46 mm with SeQuent Please, and the one-sided 97.5% upper confidence limit of the difference was 0.14 mm, achieving noninferiority of Shenqi compared with SeQuent Please (P = 0.002). In total, 12 patients developed target lesion failure (TLF) in the Shenqi group compared with 16 patients in the SeQuent Please group (10.91% versus 15.09%; P = 0.42) within 1 year. TLF was mainly driven by target lesion revascularization (9.09%) followed by target vessel-related myocardial infarction (1.82%) and cardiovascular death (0.91%) in the Shenqi group. CONCLUSIONS: Shenqi DCB was noninferior to SeQuent Please DCB for the primary endpoint of 9-month in-segment late loss. Shenqi DCB may become an attractive alternative treatment for patients with coronary ISR, withholding the need for additional stent implantation.

l-Theanine attenuates neointimal hyperplasia via suppression of vascular smooth muscle cell phenotypic modulation.

Neointimal hyperplasia is a prominent pathological phenomenon in the process of stent restenosis. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play major pathological processes involved in the development of restenosis. l-Theanine, one of the major amino acid components in green tea, has been reported to improve vascular function. Here we display the effects of l-theanine on neointima formation and the underlying mechanism. In the rat carotid-artery balloon-injury model, l-theanine greatly inhibited neointima formation and prevented VSMCs from a contractile phenotype switching to a synthetic phenotype. In vitro study showed that l-theanine significantly inhibited PDGF-BB-induced VSMC proliferation and migration, which was comparable with the effect of l-theanine on AngII-induced VSMC proliferation and migration. Western blot analysis demonstrated that l-theanine suppressed PDGF-BB and AngII-induced reduction of SMA and SM22α and increment of OPN, suggesting that l-theanine inhibited the transformation of VSMCs from contractile to the synthetic phenotype. Further experiments showed that l-theanine exhibits potential preventive effects on neointimal hyperplasia and related vascular remodeling via inhibition of phosphorylation of Elk-1 and activation of MAPK1. The present study provides the new experimental evidence that l-theanine has potential clinical application as an anti-restenosis agent for the prevention of restenosis.

Green formulation of curcumin loaded lipid-based nanoparticles as a novel carrier for inhibition of post-angioplasty restenosis.

Restenosis is one of the major complications affecting outcomes of percutaneous coronary interventions. The aims of this study were to formulate curcumin (CUR) nanoparticles by using only lipidic ingredients in the absence of any organic solvent and to determine key formulation parameters using 2-level factorial design. CUR nanoparticles were prepared using triglyceride and egg phosphatidylcholine (EPC) by high-pressure homogenization (HPH) and fully characterized regarding drug loading, particle size, zeta potential, stability, drug release profile, conductivity, viscosity, refractive index, stability, morphology and FTIR analysis. The efficacy of CUR nanoparticles in inhibiting restenosis was investigated in a rat carotid artery model. Balloon-injured rats were randomly assigned to two control (saline and empty carrier) groups and CUR nanoparticle treated group. Arterial restenosis was assessed by histomorphometric, immunohistochemical and CT angiography analyses. Optimized CUR nanoparticles with almost 70% drug entrapment, an average particle size of 58 nm, PDI < 0.2, spherical nanostructures and sustained release profile were prepared. In morphometric analysis, neointimal area and neointima/media ratio significantly decreased in the animal group received CUR nanoparticles compared with control groups. Expression of Ki67 was markedly lower in the CUR nanoformulation group. CT angiograms confirmed patency of the artery in this group. These results suggest that the new strategy of intramural delivery of CUR lipid-based nanoparticles can be considered as a novel approach to prevent neointimal hyperplasia.

Chinese Herbal Medicines for Restenosis After Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials.

Objectives: This study evaluates the efficacy of Chinese herbal medicines after percutaneous coronary intervention (PCI). Background: PCI is the primary treatment for coronary atherosclerotic heart disease (CHD). However, many patients experience restenosis within 6 months after PCI. Chinese herbal medicines are widely used in patients after PCI. Clinical studies have found that Chinese herbal medicines may prevent restenosis. Methods: Eight databases were searched for randomized controlled trials (RCTs) investigating the use of Chinese herbal medicines after PCI. The search period was from the date of database inception to June 2017. We used the Cochrane risk of bias tool to estimate the methodological quality of the studies. The primary outcome was the restenosis rate, and secondary outcomes were the angina recurrence rate and major adverse cardiac events (MACEs). Data were analyzed with RevMan 5.3, and the quality of evidence was assessed with the GRAD approach. Results: Eleven RCTs with a total of 1,383 patients were included. The major outcome was the restenosis rate, and the results showed a significant effect of Chinese herbal medicines on reduction in the rate of restenosis (risk ratio [RR] = 0.46, 95% CI: 0.35-0.60, p < 0.00001, I2 = 0%). Chinese herbal medicine treatment also decreased the angina recurrence rate (RR = 0.41, 95% CI: 0.29-0.57, p < 0.00001, I2 = 0%). The results revealed a lower rate of MACEs in the Chinese medicine group than in the control group (RR = 0.49, 95% CI: 0.34-0.71, p = 0.0001, I2 = 0%). We evaluated the quality of evidence with the GRADE system; the quality of evidence for the restenosis rate and angina was low, and the quality of evidence for MACEs was estimated to be moderate. Conclusion: According to existing research evidence, the use of Chinese herbal medicines may reduce the incidence of MACEs. Chinese herbal medicines may reduce restenosis and angina recurrence rates after PCI, but the evidence is limited.

Modulation of Cathepsin L Expression in the Coronary Arteries of Atherosclerotic Swine.

INTRODUCTION: Neointimal hyperplasia (NIH) and restenosis after percutaneous transluminal coronary angioplasty (PTCA) and intravascular stenting remain a problem on a long-term basis by causing endothelial denudation and damage to the intima and media. Vascular sterile inflammation has been attributed to the formation of NIH. Cathepsin L (CTSL), a lysosome protease, is associated with diet-induced atherogenesis. Vitamin D regulates the actions and regulatory effects of proteases and protease inhibitors in different cell types. Objectives of this study are to evaluate the modulatory effect of vitamin D on CTSL activity in post-PTCA coronary arteries of atherosclerotic swine. METHODS: Yucatan microswine were fed with high-cholesterol atherosclerotic diets. The swine were stratified to receive three diets: (1) vitamin D-deficient diet, (2) vitamin D-sufficient diet, and (3) vitamin D-supplement diet. After 6 mo, PTCA was performed in the left circumflex coronary artery (LCx). After 1 y, angiography and optical coherence tomography imaging were performed, and swine was euthanized. Coronary arteries were embedded in paraffin. Tissue sections were stained with hematoxylin and eosin. Expression of Ki67 and CTSL were evaluated by immunofluorescence. RESULTS: Increased number of Ki67 + cells were observed in the postangioplasty LCx in vitamin D-deficient compared with vitamin D-sufficient or vitamin D-supplemented swine. Notably, the expression of CTSL was significantly increased in postangioplasty LCx of vitamin D-deficient swine compared with the vitamin D-sufficient or vitamin D-supplemented animal groups. CONCLUSIONS: Increased expression of CTSL correlates with the formation of NIH in the PTCA-injured coronary arteries. However, in the presence of sufficient or supplemented levels of vitamin D in the blood, CTSL expression was significantly reduced.

Detoxification and activating blood circulation decoction reduces restenosis involving the TLR4/NF-κB pathway after balloon injury.

Restenosis is a major problem after percutaneous coronary intervention (PCI) treatment. Inflammation is one of the major core mechanisms involved in the occurrence of restenosis, and plays an important role in intimal hyperplasia. Detoxification and activating blood circulation decoction (DABCD) is a traditional Chinese medicine that is used in the treatment and prevention of atherosclerotic and inflammatory diseases. Our previous studies demonstrated that DABCD-mediated cardioprotection involves anti-inflammatory mechanisms and could be developed as a novel drug for the treatment of vascular smooth muscle cell (VSMC) proliferation and aortic restenosis. A rat model of postoperative restenosis after PCI was generated by balloon injury to determine the protective effects and potential mechanisms of DABCD. The injured segments of aortae were collected on days 14 and 28 after the operation to observe the morphological changes in the vascular structure and measure the proportion of inflammatory factors in plasma and vascular tissues, as well as test the proliferative activity of VSMCs. The expression of related proteins, namely, Toll-like receptor (TLR) 4 and nuclear factor (NF)-κB, in the mechanistic study was clarified by western blot analysis. We tested the hypothesis that the cardioprotective effects of DABCD on aortic restenosis are associated with the inhibition of aortic intimal hyperplasia in this model. Our results showed that DABCD has protective effect on rat aortic restenosis and the anti-inflammatory mechanism of DABCD on balloon-induced restenosis in rat may be due to its ability to inhibit TLR4-mediated NF-κB signaling pathways. DABCD may be a potential therapeutic agent against restenosis.

Fufang-Zhenzhu-Tiaozhi Capsule reduces restenosis via the downregulation of NF-kappaB and inflammatory factors in rabbits.

BACKGROUND: To investigate the effects of a Chinese herbal medicine Fufang-Zhenzhu Tiaozhi Capsule (FTZ) on restenosis and elucidate the mechanism of action. METHODS: A restenosis model was established by balloon rubbing the endothelium of the abdominal aorta followed by high fat diet. Rabbits were divided into blank control group, restenosis group, FTZ group (0.66 mg/kg/day), atorvastatin group (5 mg/kg/day) and FTZ + atorvastatin group (n = 8). Vascular stenosis was analyzed by X-ray. Serum levels of chemokines and cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were measured by ELISA. The levels of NF-κB, IκB-α, P-IκBα, IKK-α, and P-IKKα/ß from injured abdominal arteries were detected by Western blotting. RESULTS: Restenosis was induced successfully via abdominal artery balloon injuries and high fat diet. Restenosis was significantly decreased in FTZ group compared with restenosis group (P < 0.05). FTZ group had markedly reduced serum lipid levels (P < 0.05). In addition, the levels of TNF-α, IL-1, IL-6, IL-8, IL-12, ICAM-1 and MCP-1 decreased by FTZ treatment (P < 0.05). The expression of NF-κB in the atherosclerotic lesions was significantly attenuated in FTZ group (P < 0.05). CONCLUSION: FTZ could reduce restenosis via reducing NF-κB activity and inflammatory factor expression within the atherosclerotic lesion in a rabbit restenosis model. FTZ may be a new therapeutic agent for restenosis.

Vitamin D and macrophage polarization in epicardial adipose tissue of atherosclerotic swine.

Vitamin D functions as a potent immunomodulator by interacting with many immune cells however, its role in regulating inflammation in the epicardial adipose tissue (EAT) is unclear. In the EAT of atherosclerotic microswine that were fed with deficient, sufficient or supplemented levels of vitamin D, we evaluated the phenotype of the macrophages. Vitamin D treatment was continued for 12 months and serum 25(OH)D levels were measured regularly. Infiltration of M1/M2 macrophage was investigated by immunostaining for CCR7 and CD206, respectively in conjunction with a pan macrophage marker CD14. Significant difference in the number of CCR7+ cells was observed in the EAT from vitamin D-deficient swine compared to vitamin D-sufficient or -supplemented swine. Expression of CD206 correlated with high levels of serum 25(OH)D indicating a significant increase in M2 macrophages in the EAT of vitamin D-supplemented compared to -deficient swine. These findings suggest that vitamin D-deficiency exacerbates inflammation by increasing pro-inflammatory M1 macrophages, while vitamin D-supplementation attenuates the inflammatory cytokines and promotes M2 macrophages in EAT. This study demonstrates the significance of vitamin D mediated inhibition of macrophage mediated inflammation in the EAT during coronary intervention in addition to its immunomodulatory role. However, additional studies are required to identify the cellular mechanisms that transduce signals between macrophages and smooth muscle cells during restenosis in the presence and absence of vitamin D.

The regulatory role of curcumin on platelet functions.

Curcumin, the main ingredient of Curcuma longa L., has been used as a spice and as a herbal medicine with different therapeutic characteristics for centuries in Asian countries. This phytochemical has been shown to possess beneficial antiplatelet activity that has introduced it as a promising candidate for the treatment of thromboembolism, atherothrombosis, and inflammatory diseases. Platelet dysfunction under different circumstances may lead to cardiovascular disease, and curcumin has been shown to have beneficial effects on platelet dysfunction in several studies. Therefore, this narrative review is aimed to summarize available evidence on the antiplatelet activity of curcumin and related molecular mechanisms for this activity.