Linarin Ameliorates Restenosis After Vascular Injury in Type 2 Diabetes Mellitus via Regulating ADAM10-Mediated Notch Signaling Pathway.

Vascular lesions frequently arise as complication in patients diagnosed with diabetes mellitus (DM). Presently, percutaneous coronary intervention (PCI) and antithrombotic therapy serve as primary treatments. However, in-stent restenosis persists as a challenging clinical issue following PCI, lacking sustained and effective treatment. Linarin (LN) exhibits diverse pharmacological activities and is regarded as a potential drug for treating various diseases, including DM. But its specific role in restenosis after vascular injury in DM patients remains unclear. A rat model of diabetes-related restenosis was established to evaluate the role of LN on neointimal hyperplasia. Vascular smooth muscle cells (VSMCs) stimulated by high glucose (HG, 30 mM) underwent LN treatment. Additionally, an overexpression plasmid of A disintegrin and metalloproteinases (ADAM10) was constructed to transfect VSMCs. We employed CCK-8, Brdu, wound-healing scratch, and transwell migration assays to evaluate the proliferation and migration of VSMCs. Furthermore, western blot and immunofluorescence assays were utilized to investigate the expressions of ADAM10 and the downstream Notch signaling pathway in vivo and in vitro models. LN notably alleviated intimal hyperplasia after vascular injury in DM rats and reduced the protein expression of ADAM10, alongside its downstream Notch1 signaling pathway-related proteins (Notch1, NICD and Hes1) in rat carotid artery tissues. LN effectively suppressed the proliferation and migration of VSMCs induced by HG, downregulating the protein expression of ADAM10, Notch1, NICD and Hes1. Moreover, our findings indicated that ADAM10 overexpression significantly reversed LN's effects on proliferation, migration, and the expression of Notch1 signaling pathway-related proteins in HG-treated VSMCs. LN demonstrates potential therapeutic efficacy in addressing restenosis after diabetic-related vascular injury, with the ADAM10 mediated Notch signaling pathway playing a pivotal role.

REDV-Functionalized Recombinant Spider Silk for Next-Generation Coronary Artery Stent Coatings: Hemocompatible, Drug-Eluting, and Endothelial Cell-Specific Materials.

Coronary artery stents are life-saving devices, and millions of these devices are implanted annually to treat coronary heart disease. The current gold standard in treatment is drug-eluting stents, which are coated with a biodegradable polymer layer that elutes antiproliferative drugs to prevent restenosis due to neointimal hyperplasia. Stenting is commonly paired with systemic antiplatelet therapy to prevent stent thrombosis. Despite their clinical success, current stents have significant limitations including inducing local inflammation that drives hyperplasia; a lack of hemocompatibility that promotes thrombosis, increasing need for antiplatelet therapy; and limited endothelialization, which is a critical step in the healing process. In this research, we designed a novel material for use as a next-generation coating for drug-eluting stents that addresses the limitations described above. Specifically, we developed a recombinant spider silk material that is functionalized with an REDV cell-adhesive ligand, a peptide motif that promotes specific adhesion of endothelial cells in the cardiovascular environment. We illustrated that this REDV-modified spider silk variant [eADF4(C16)-REDV] is an endothelial-cell-specific material that can promote the formation of a near-confluent endothelium. We additionally performed hemocompatibility assays using human whole blood and demonstrated that spider silk materials exhibit excellent hemocompatibility under both static and flow conditions. Furthermore, we showed that the material displayed slow enzyme-mediated degradation. Finally, we illustrated the ability to load and release the clinically relevant drug everolimus from recombinant spider silk coatings in a quantity and at a rate similar to that of commercial devices. These results support the use of REDV-functionalized recombinant spider silk as a coating for drug-eluting stents.

The Effect of Angiotensin Receptor Blockers on In-Stent Restenosis After Stent Implantation: A Meta-Analysis.

AIM: Angiotensin receptor blockers (ARBs) have been shown to inhibit restenosis in vitro and in vivo, but the evidence found in humans is inconsistent. This study aimed to evaluate the effectiveness of ARBs in preventing in-stent restenosis after percutaneous coronary intervention (PCI). METHOD: Databases including the Cochrane Library, MEDLINE, Web of Science, EMBASE, and CNKI were searched to collect randomised controlled trials on ARBs inhibiting restenosis that were published before October 2022. A total of 1,056 patients enrolled in eight trials were included in the study. RESULTS: The ARBs group showed lower target lesion revascularisation than the control group (RR 0.54; 95% CI 0.34-0.86; p=0.01), but the restenosis incidence between these two groups was not statistically significant (RR 0.85; 95% CI 0.65-1.11; p>0.05). CONCLUSION: This study found that ARBs might have a potential effect on reducing target lesion revascularisation after PCI in coronary heart disease patients but has no impact on angiographic restenosis.

A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.

Drug-eluting stent implantation suppresses the excessive proliferation of smooth muscle cells to reduce in-stent restenosis. However, the efficacy of drug-eluting stents remains limited due to delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here, we show that a drug-free coating formulation functionalized with tailored recombinant humanized type III collagen exerts one-produces-multi effects in response to injured tissue following stent implantation. We demonstrate that the one-produces-multi coating possesses anticoagulation, anti-inflammatory, and intimal hyperplasia suppression properties. We perform transcriptome analysis to indicate that the drug-free coating favors the endothelialization process and induces the conversion of smooth muscle cells to a contractile phenotype. We find that compared to drug-eluting stents, our drug-free stent reduces in-stent restenosis in rabbit and porcine models and improves vascular neointimal healing in a rabbit model. Collectively, the one-produces-multi drug-free system represents a promising strategy for the next-generation of stents.

Hypercholesterolemia exacerbates in-stent restenosis in rabbits: Studies of the mitigating effect of stent surface modification with a CD47-derived peptide.

BACKGROUND AND AIMS: Hypercholesterolemia (HC) has previously been shown to augment the restenotic response in animal models and humans. However, the mechanistic aspects of in-stent restenosis (ISR) on a hypercholesterolemic background, including potential augmentation of systemic and local inflammation precipitated by HC, are not completely understood. CD47 is a transmembrane protein known to abort crucial inflammatory pathways. Our studies have examined the interrelation between HC, inflammation, and ISR and investigated the therapeutic potential of stents coated with a CD47-derived peptide (pepCD47) in the hypercholesterolemic rabbit model. METHODS: PepCD47 was immobilized on metal foils and stents using polybisphosphonate coordination chemistry and pyridyldithio/thiol conjugation. Cytokine expression in buffy coat-derived cells cultured over bare metal (BM) and pepCD47-derivatized foils demonstrated an M2/M1 macrophage shift with pepCD47 coating. HC and normocholesterolemic (NC) rabbit cohorts underwent bilateral implantation of BM and pepCD47 stents (HC) or BM stents only (NC) in the iliac location. RESULTS: A 40 % inhibition of cell attachment to pepCD47-modified compared to BM surfaces was observed. HC increased neointimal growth at 4 weeks post BM stenting. These untoward outcomes were mitigated in hypercholesterolemic rabbits treated with pepCD47-derivatized stents. Compared to NC animals, inflammatory cytokine immunopositivity and macrophage infiltration of peri-strut areas increased in HC animals and were attenuated in HC rabbits treated with pepCD47 stents. CONCLUSIONS: Augmented inflammatory responses underlie severe ISR morphology in hypercholesterolemic rabbits. Blockage of initial platelet and leukocyte attachment to stent struts through CD47 functionalization of stents mitigates the pro-restenotic effects of hypercholesterolemia.

Is it time for a retinoic acid-eluting stent or retinoic acid-coated balloon? Insights from experimental studies of systemic and local delivery of retinoids.

Although the incidence of restenosis and stent thrombosis has substantially declined during the last decades, they still constitute the two major causes of stent failure. These complications are partially attributed to the currently used cytostatic drugs, which can cause local inflammation, delay or prevent re-endothelialization and essentially cause arterial cell toxicity. Retinoic acid (RA), a vitamin A (retinol) derivative, is a naturally occurring substance used for the treatment of cell proliferation disorders. The agent has pleiotropic effects on vascular smooth muscle cells and macrophages: it influences the proliferation, migration, and transition of smooth muscle cells to other cell types and modulates macrophage activation. These observations are supported by accumulated evidence from in vitro and in vivo experiments. In addition, systemic and topical administration of RA can decrease the development of atherosclerotic plaques and reduce or inhibit restenosis after vascular injury (caused by embolectomy, balloon catheters, or ligation of arteries) in various experimental models. Recently, an RA-drug eluting stent (DES) has been tested in an animal model. In this review, we explore the effects of RA in atherosclerosis and the potential of the local delivery of RA through an RA-DES or RA-coated balloon for targeted therapeutic percutaneous vascular interventions. Despite promising published results, further experimental study is warranted to examine the safety and efficacy of RA-eluting devices in vascular artery disease.

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.

Application of Nanoliposome Alprostadil in the Perioperative Period of Percutaneous Coronary Intervention to Reduce In-Stent Restenosis: A Systematic Review and Meta-Analysis.

Background: In-stent restenosis (ISR) is a common complication after percutaneous coronary intervention (PCI) surgery for patients with coronary atherosclerotic heart disease (CHD). Reports indicate alprostadil may reduce ISR, and this study aimed at reviewing and summarizing the effect of nanoliposome alprostadil on ISR by meta-analysis. Methods: Articles were searched from databases, and meta-analysis was performed in Review Manager software. Funnel plots were performed to evaluate the publication bias, and sensitivity analysis was performed to determine the robustness of the overall treatment effects. Results: Initially, 113 articles were identified, and 5 studies of 463 subjects were included for analysis eventually. The primary endpoint, i.e., the occurrence of ISR after PCI, occurred in 11.91% of the alprostadil treatment group (28 from 235 patients) vs. 21.49% of the conventional treatment group (49 from 228 patients) and showed a statistical significance in our pooled data (χ2 = 7.654, P=0.006), while there was no statistically significant difference in all of the separate studies. We observed no statistical methodological heterogeneity among the studies (P=0.64, I2 ≈ 0%). The pooled odds ratio (OR) of the occurrence of ISR was 49% in a fixed-effect model, and the 95% confidence boundary (95% CI) was 29% to 81%. The funnel plot did not show serious publication bias, and sensitivity analysis showed well robustness of the overall treatment effect. Discussion. In conclusion, the early application of nanoliposome alprostadil after PCI could effectively reduce the occurrence of ISR, and the overall effect of alprostadil treatment in reducing ISR after PCI was relatively stable.

"Spongy skin" as a robust strategy to deliver 4-octyl itaconate for conducting dual-regulation against in-stent restenosis.

The valid management of inflammation and precise inhibition of smooth muscle cells (SMCs) is regarded as a promising strategy for regulating vascular responses after stent implantation, yet posing huge challenges to current coating constructions. Herein, we proposed a spongy cardiovascular stent for the protective delivery of 4-octyl itaconate (OI) based on a "spongy skin" approach, and revealed the dual-regulation effects of OI for improving vascular remolding. We first constructed a "spongy skin" onto poly-l-lactic acid (PLLA) substrates, and realized the protective loading of OI with the highest dosage of 47.9 µg/cm2. Then, we verified the remarkable inflammation mediation of OI, and surprisingly revealed that the OI incorporation specifically inhibited SMC proliferation and phenotype switching, which contributed to the competitive growth of endothelial cells (EC/SMC ratio âˆ¼ 5.1). We further demonstrated that OI at a concentration of 25 µg/mL showed significant suppression of the TGF-ß/Smad pathway of SMCs, leading to the promotion of contractile phenotype and reduction of extracellular matrix. In vivo evaluation indicated that the successful delivery of OI fulfilled the inflammation regulation and SMCs inhibition, therefore suppressing the in-stent restenosis. This "spongy skin" based OI eluting system may serve as a new strategy for improving vascular remolding, and provides a potential concept for the treatment of cardiovascular diseases.

Clinical expert consensus document on drug-coated balloon for coronary artery disease from the Japanese Association of Cardiovascular Intervention and Therapeutics.

Drug-coated balloon (DCB) technology was developed to deliver the antiproliferative drugs to the vessel wall without leaving any permanent prosthesis or durable polymers. The absence of foreign material can reduce the risk of very late stent failure, improve the ability to perform bypass-graft surgery, and reduce the need for long-term dual antiplatelet therapy, potentially reducing associated bleeding complications. The DCB technology, like the bioresorbable scaffolds, is expected to be a therapeutic approach that facilitates the "leave nothing behind" strategy. Although newer generation drug-eluting stents are the most common therapeutic strategy in modern percutaneous coronary interventions, the use of DCB is steadily increasing in Japan. Currently, the DCB is only indicated for treatment of in-stent restenosis or small vessel lesions (< 3.0 mm), but potential expansion for larger vessels (≥ 3.0 mm) may hasten its use in a wider range of lesions or patients with obstructive coronary artery disease. The task force of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) was convened to describe the expert consensus on DCBs. This document aims to summarize its concept, current clinical evidence, possible indications, technical considerations, and future perspectives.

High on-aspirin treatment platelet reactivity and restenosis after percutaneous coronary intervention: results of the Intracoronary Stenting and Antithrombotic Regimen-ASpirin and Platelet Inhibition (ISAR-ASPI) Registry.

OBJECTIVE: The aim of this study was to assess the association between high on-aspirin treatment platelet reactivity (HAPR) and the subsequent risk of restenosis after percutaneous coronary intervention (PCI) with predominantly drug-eluting stents. BACKGROUND: The association between HAPR and subsequent risk of restenosis after PCI is unclear. METHODS: This study included 4839 patients undergoing PCI (02/2007-12/2011) in the setting of the Intracoronary Stenting and Antithrombotic Regimen-ASpirin and Platelet Inhibition (ISAR-ASPI) registry. Platelet function was assessed with impedance aggregometry using the multi-plate analyzer immediately before PCI and after intravenous administration of aspirin (500 mg). The primary outcome was clinical restenosis, defined as target lesion revascularization at 1 year. Secondary outcomes included binary angiographic restenosis and late lumen loss at 6- to 8-month angiography. RESULTS: The upper quintile cut-off of platelet reactivity measurements (191 AU × min) was used to categorize patients into a group with HAPR (platelet reactivity > 191 AU × min; n = 952) and a group without HAPR (platelet reactivity ≤ 191 AU × min; n = 3887). The primary outcome occurred in 94 patients in the HAPR group and 405 patients without HAPR (cumulative incidence, 9.9% and 10.4%; HR = 0.96, 95% CI 0.77-1.19; P = 0.70). Follow-up angiography was performed in 73.2% of patients. There was no difference in binary restenosis (15.2% vs. 14.9%; P = 0.79) or late lumen loss (0.32 ± 0.57 vs. 0.32 ± 0.59 mm; P = 0.93) between patients with HAPR versus those without HAPR. CONCLUSIONS: This study did not find an association between HAPR, measured at the time of PCI, and clinical restenosis at 1 year after PCI.

miRNA­92a inhibits vascular smooth muscle cell phenotypic modulation and may help prevent in­stent restenosis.

The modulation of vascular smooth muscle cell (VSMC) phenotype during cellular proliferation and migration may represent a potential therapeutic approach for vascular intimal hyperplasia prevention. However, the precise role of this process in VSMC biology and remodeling remains unclear. In the present study, western blotting, PCR, MTT and Transwell assays were used to analyze related protein and mRNA expression, cell viability and cell migration, respectively. It was demonstrated that miR­92a modulated VSMCs into a synthetic phenotype via the Kruppel­like factor 4 (KLF4) pathway. Targeting microRNA (miRNA/miR)­92a in VSMCs using a KLF4 inhibitor suppressed the synthetic phenotype and inhibited VSMC proliferation and migration. To further confirm this finding, the expression levels of miR­92a were measured in patients undergoing coronary artery intervention. The serum miR­92a expression levels were significantly higher in patients with in­stent restenosis (ISR) compared with those in patients without ISR, whereas KLF4 expression was significantly reduced in the non­ISR group. Bioinformatic analysis and promoter­luciferase reporter assays were used to examine the regulatory mechanisms underlying KLF4 expression. KLF4 was demonstrated to be transcriptionally upregulated by miR­92a in VSMCs. miRNA transfection was also performed to regulate the level of miR­92a expression. miR­92a overexpression inhibited VSMC proliferation and migration, and also increased the mRNA and protein expression levels of certain differentiated VSMC­related genes. Finally, miR­92a inhibition promoted the proliferation and migration of VSMCs, which could be reversed using a KLF4 inhibitor. Collectively, these results indicated that the local delivery of a KLF4 inhibitor may act as a novel therapeutic option for the prevention of ISR.

The potential function of SP1 and CPPED1 in restenosis after percutaneous coronary intervention.

OBJECTIVES: Impacts of molecular pathways have been discussed recently on restenosis after percutaneous coronary intervention (PCI). Hence, this study aimed to explore the impact of calcineurin-like phosphoesterase domain containing 1 (CPPED1) and specificity protein 1 (SP1) on restenosis after PCI. METHODS: A carotid balloon injury rat model was established, followed by western blot analysis of SP1 and CPPED1 expression in carotid artery (CA) tissues. After SP1 and CPPED1 were overexpressed, the neointimal hyperplasia and luminal stenosis were assessed. In addition, EPC underwent hypoxia/reoxygenation (H/R) treatment to construct an endothelial injury cell model. Then, cell proliferation, apoptosis, intracellular reactive oxygen species (ROS), and Ca2+ concentration were detected with cell counting kit-8 (CCK-8), flow cytometry, Chloromethyl-2'7'-dichlorofluorescein diacetate (CM-H2DCFDA) penetrant, and Fluo-4 AM staining, respectively. The binding relationship between SP1 and CPPED1 was verified by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: SP1 and CPPED1 were lowly expressed in the model rats with carotid balloon injury. Mechanistically, SP1 bound to the promoter region of CPPED1 to activate CPPED1 expression. Overexpressing SP1 or CPPED1 lowered neointimal formation and restenosis rate, thus promoting the recovery of carotid balloon injury in rats. Meanwhile, SP1 and CPPED1 upregulation reduced ROS levels, Ca2+ concentration, and apoptosis of EPCs, accompanied by accelerated EPC viability. CONCLUSIONS: SP1 or CPPED1 overexpression reduced neointimal formation and restenosis rate in carotid balloon injury.

Coupled benefits of nanotopography and titania surface chemistry in fostering endothelialization and reducing in-stent restenosis in coronary stents.

Recent advances in coronary stents have all been distinctively focused towards directing re-endothelialization with minimal in-stent restenosis, potentially via alterations in surface topographical cues, for augmenting the efficacy of vascular implants. This perspective was proven by our group utilizing a simple and easily scalable nanosurface modification strategy on metallic stents devoid of any drugs or polymers. In the present work, we explore the impact of surface characteristics in modulating this cell response in-vitro and in-vivo, using titania coated cobalt-chromium (CC) stents, with and without nanotopography, in comparison to commercial controls. Interestingly, titania nanotopography facilitated a preferential cell response in-vitro as against the titania coated and bare CC surfaces, which can be attributed to surface topography, hydrophilicity, and roughness. This in turn altered the cellular adhesion, proliferation and focal contact formations of endothelial and smooth muscle cells. We also demonstrate that titania nanotexturing plays a pivotal role in fostering rapid re-endothelialization with minimal neointimal hyperplasia, leading to excellent in-vivo patency of CC stents post 8 weeks implantation in rabbit iliac arteries, in comparison to bare CC, nano-less titania coated CC, and commercial drug-eluting stents (CC DES), without administering antiplatelet agents. This exciting result for the drug and polymer-free titania nanotextured stents, in the absence of platelet therapy, reveals the possibility of proposing an alternative to clinical DES for coronary stenting.

Treatment effect of metformin combined with atorvastatin in reducing in-stent restenosis after percutaneous coronary intervention in coronary artery disease patients with type 2 diabetic patients.

To investigate the effectiveness of metformin and atorvastatin in preventing in-stent restenosis (ISR) on coronary patients with type 2 diabetes mellitus with percutaneous coronary intervention within 8 to 12 months after rapamycin-eluting stent implantation. A total of 1278 consecutive patients implanted with rapamycin-eluting stent from January 2012 to December 2019, who underwent coronary computed tomography or coronary angiography within 8 to 12 months. The patients were categorized into atorvastatin 20 mg, or atorvastatin 20 mg + metformin 1.5/d, or atorvastatin 40 mg + metformin 1.5/d groups. The clinical characteristics of the 3 groups were compared. The correlation between variables and ISR was analyzed. A total of 701 patients participated in the study. The ratio of ISR/nonstenosis (P = .039) and fasting blood sugar (P = .001) differed significantly in the 3 groups. Logistic regression showed that d, L, different therapeutic agents, and dosage groups were independent risk factors of ISR. The longer L and smaller d may increase ISR incidence with 8 to 12 months after percutaneous coronary intervention. Both metformin and atorvastatin are beneficial in reducing stent restenosis by a dose-dependent manner. An increasing dose of atorvastatin and a combination of metformin decreases the incidence of ISR in patients.

Exosome-Loaded Pro-efferocytic Vascular Stent with Lp-PLA2-Triggered Release for Preventing In-Stent Restenosis.

The efferocytosis defect is regarded as a pivotal event of atherosclerosis. The failure to clear apoptotic cells in atherosclerotic plaques under vascular stents causes a failure to resolve the inflammation underneath. However, efferocytosis repair is still confined to nonstenting therapeutics. Here, we identified a pro-efferocytotic agent and accordingly developed a bioresponsive pro-efferocytotic vascular stent aimed for poststenting healing. Exosomes derived from mesenchymal stem cells were found to be able to regulate efferocytosis via SLC2a1, STAT3/RAC1, and CD300a pathways and modulate foam cell formation processes through a CD36-mediated pathway. Pro-efferocytotic exosomes were encapsulated into liposome-based multivesicular chambers and grafted onto vascular stents. The multivesicular vesicles were able to release exosomes under the Lp-PLA2 environment. Compared to bare metal stents, exosome-stents in the presence of Lp-PLA2 enhanced the ratio of apoptotic cell clearance and reduced the neointimal thickness in the mal-efferocytotic rat model. Overall, we identified a pro-efferocytic agent─exosomes that are able to regulate target cells via multiple signaling pathways and are good candidates to serve complex pathological environments, and this bioresponsive pro-efferocytotic vascular stent is an attractive approach for prevention of poststenting complications.

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.

Bioinspired Vascular Stents with Microfluidic Electrospun Multilayer Coatings for Preventing In-Stent Restenosis.

In-stent restenosis (ISR) is seriously affecting the long-term prognosis of vascular interventional therapy and leading to enormous medical burdens. Great efforts have been devoted to developing functional vascular stents with desired features and properties for effective ISR prevention. Here, a multifunctional bionic vascular stent with designed coatings prepared using microfluidic electrospinning technology is presented. Such stents are composed of biocompatible, drug-loaded methylacrylated gelatin-polyethylene glycol diacrylate (GelMA-PEGDA) and polycaprolactone composite nanofibers on 316L stainless steel stents by an easy-to-operate step-by-step spraying method. Benefitting from the addition of polydopamine during the fabrications, the drug-loaded composite nanofibers can adhere well to both the stent and the vascular wall. Furthermore, as the inner fibrous layer of the stent contacting the lumen is equipped with heparin-vascular endothelial growth factor (Hep-VEGF), it plays an anticoagulation role and promotes the growth of endothelial cells; while the outer layer contacts the vascular wall and releases rapamycin slowly, which can restrain smooth muscle proliferation. By implanting this into the rabbit carotid artery, the multi-functional bionic demonstrates that the vascular stent can achieve good anti-thrombosis and in-stent restenosis effects, which indicates its potential values in vascular intervention and other biomedical fields.

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.