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.

Morphological characteristics of in-stent restenosis with different degrees of area stenosis: an optical coherence tomography study.

The morphological characteristics of in-stent restenosis (ISR) in relation to varying degrees of area stenosis have not been comprehensively examined. This study aimed to explore the tissue characteristics of patients experiencing ISR with different degrees of area stenosis through the utilization of optical coherence tomography (OCT). In total, 230 patients with ISR who underwent OCT were divided into the following three groups: area stenosis (AS) < 70% (n = 26); 70-80% (n = 119) and AS ≥ 80% (n = 85). Among the 230 patients, the clinical presentation as stable angina was 61.5% in AS < 70%, followed by 47.2% in 70% < AS ≤ 80%, and 31.8% in AS ≥ 80% (P = 0.010). The OCT findings showed that heterogeneous neointima, ISNA, LRP, neointima rupture, TCFA-like pattern, macrophage infiltration, red and white thrombus was more common with AS increased. Ordinal logistic regression analysis showed that higher AS was associated with previous dyslipidemia (odds ratio [OR], 4.754; 95% confidence interval [CI], 1.419-15.927, P = 0.011), neointimal rupture (OR: 3.640; 95% CI, 1.169-11.325, P = 0.026), red thrombus (OR: 4.482; 95% CI, 1.269-15.816, P = 0.020) and white thrombus (OR: 5.259; 95% CI, 1.660-16.659, P = 0.005). Patients with higher degrees of area stenosis in the context of ISR exhibited a greater number of discernible morphological characteristics as identified through OCT analysis. Furthermore, previous dyslipidemia, neointimal rupture, white thrombus and red thrombus were highly associated with and the progression of ISR lesions.

Histological Features of In-Stent Restenosis after Iliac Vein Thrombus Removal and Stent Placement in a Goat Model.

PURPOSE: To establish an animal model for in-stent restenosis (ISR) after postthrombotic iliac vein stent placement and characterize histopathological changes in tissue within the stented vein. MATERIALS AND METHODS: Iliac vein thrombosis was induced using balloon occlusion and thrombin injection in 8 male Boer goats. Mechanical thrombectomy and iliac vein stent placement were performed 3 days after thrombosis induction. Restenosis was evaluated by venography and optical coherence tomography (OCT) at 1 and 8 weeks after stent placement, and stent specimens were taken for pathological examination after the animals were euthanized. RESULTS: Thrombosis induction was successful in all 8 goats, with >80% iliac vein occlusion. After thrombus removal, OCT revealed considerable venous intimal thickening and a small number of mural thrombi. Neointimal hyperplasia with thrombus formation was observed in all goats 1 week after stent implantation; the degree of ISR was 15%-33%. At 8 weeks, the degree of ISR was 21%-32% in 3 goats, and stent occlusion was observed in 1 goat. At 1 week, the neointima predominantly consisted of fresh thrombi. At 8 weeks, proliferplastic fibrotic tissue and smooth muscle cells (SMCs) were predominant, and the stent surfaces were endothelialized in 2 of 3 goats and partially endothelialized in 1 goat. CONCLUSIONS: In the goat model, postthrombotic neointimal hyperplasia in the venous stent may result from time-dependent thrombus formation and organization, accompanied by migration and proliferation of SMCs, causing ISR. These results provide a basis to further explore the mechanism of venous ISR and promote the development of venous stents that reduce neointimal hyperplasia.

Effects of exenatide on coronary stent's endothelialization in subjects with type 2 diabetes: a randomized controlled trial. The Rebuild study.

BACKGROUND: Subjects with type 2 diabetes (T2D) have a higher risk of in-stent restenosis and stent thrombosis. The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been suggested to induce several effects on the vasculature that may reduce the risk of stent failure following an angioplasty. The aim of this study is to evaluate the effect of the GLP-1R agonist exenatide on endothelialization of a modern drug-eluting stent (DES) in subjects with T2D. METHODS: 38 subjects with T2D who were eligible for revascularization with implantation of DES were randomized to treatment with exenatide (once weekly) plus standard treatment, or to standard treatment alone. After 12 weeks, a new coronary angiography was performed to evaluate the percentage of strut coverage (primary endpoint) and the presence of neo-atherosclerosis by optical coherence tomography. This study was approved by the Stockholm's Ethical Review Board. RESULTS: The two groups were well balanced regarding baseline clinical characteristics. Strut coverage was 95% (88.7-98.5%) in the exenatide group and 91.4% (88.8-98.5%) in the control group (p = 0.692). There were no significant differences between groups neither in the thickness of neo-intima (0.2 mm in both groups, p = 0.471), nor the maximal in-stent obstruction by neo-intima (15.5% in exenatide group vs 14.7% in control group, p = 0.801). No significant differences were detected in the rate of target lesion revascularization between groups (p = 0.224). CONCLUSION: Twelve weeks treatment with exenatide did not lead to a significantly better stent coverage in people with T2D. No significant differences in the occurrence of neo-atherosclerosis were detected between groups. TRIAL REGISTRATION: The study was registered at www. CLINICALTRIALS: gov (Rebuild Study, NCT02621489).

Association of LDL-C level with neoatherosclerosis and plaque vulnerability in patients with late restenosis: an optical coherence tomography study.

Neoatherosclerosis (NA) is a significant contributor to late stent failure; however, predictors of late in-stent restenosis (ISR) with NA have not been systematically reported. This study aimed to identify predictors of NA incidence and plaque vulnerability in patients with late ISR and the role of low-density lipoprotein cholesterol (LDL-C) levels in this process. A total of 216 patients with 216 lesions who underwent optical coherence tomography (OCT) before interventional procedure for late drug-eluting stent ISR were enrolled and divided into NA and non-NA groups based on OCT findings. Results showed that higher LDL-C levels were associated with NA, thin-cap fibroatheroma (TCFA), intimal disruption, plaque erosion, and thrombosis. Multivariate regression analysis revealed that the LDL-C level was an independent risk factor for NA and TCFA. The LDL-C levels exhibited a significant predictive value for NA and TCFA, surpassing other factors such as stent age and other lipid types. In conclusion, a high LDL-C level is an independent predictor of NA incidence and plaque vulnerability in patients with late ISR.

Multilevel Assessment of Stent-Induced Inflammation in the Adjacent Vascular Tissue.

A recent U.S. Food and Drug Administration report presented the currently available scientific information related to biological response to metal implants. In this work, a multilevel approach was employed to assess the implant-induced and biocorrosion-related inflammation in the adjacent vascular tissue using a mouse stent implantation model. The implications of biocorrosion on peri-implant tissue were assessed at the macroscopic level via in vivo imaging and histomorphology. Elevated matrix metalloproteinase activity, colocalized with the site of implantation, and histological staining indicated that stent surface condition and implantation time affect the inflammatory response and subsequent formation and extent of neointima. Hematological measurements also demonstrated that accumulated metal particle contamination in blood samples from corroded-stetted mice causes a stronger immune response. At the cellular level, the stent-induced alterations in the nanostructure, cytoskeleton, and mechanical properties of circulating lymphocytes were investigated. It was found that cells from corroded-stented samples exhibited higher stiffness, in terms of Young's modulus values, compared to noncorroded and sham-stented samples. Nanomechanical modifications were also accompanied by cellular remodeling, through alterations in cell morphology and stress (F-actin) fiber characteristics. Our analysis indicates that surface wear and elevated metal particle contamination, prompted by corroded stents, may contribute to the inflammatory response and the multifactorial process of in-stent restenosis. The results also suggest that circulating lymphocytes could be a novel nanomechanical biomarker for peri-implant tissue inflammation and possibly the early stage of in-stent restenosis. Large-scale studies are warranted to further investigate these findings.

In-stent restenosis is associated with proliferative skin healing and specific immune and endothelial cell profiles: results from the RACHEL trial.

Introduction: In-stent restenosis (ISR) is a major challenge in interventional cardiology. Both ISR and excessive skin healing are aberrant hyperplasic responses, which may be functionally related. However, the cellular component underlying ISR remains unclear, especially regarding vascular homeostasis. Recent evidence suggest that novel immune cell populations may be involved in vascular repair and damage, but their role in ISR has not been explored. The aims of this study is to analyze (i) the association between ISR and skin healing outcomes, and (ii) the alterations in vascular homeostasis mediators in ISR in univariate and integrative analyses. Methods: 30 patients with ≥1 previous stent implantation with restenosis and 30 patients with ≥1 stent without restenosis both confirmed in a second angiogram were recruited. Cellular mediators were quantified in peripheral blood by flow cytometry. Skin healing outcomes were analyzed after two consecutive biopsies. Results: Hypertrophic skin healing was more frequent in ISR patients (36.7%) compared to those ISR-free (16.7%). Patients with ISR were more likely to develop hypertrophic skin healing patterns (OR 4.334 [95% CI 1.044-18.073], p=0.033), even after correcting for confounders. ISR was associated with decreased circulating angiogenic T-cells (p=0.005) and endothelial progenitor cells (p<0.001), whereas CD4+CD28null and detached endothelial cells counts were higher (p<0.0001 and p=0.006, respectively) compared to their ISR-free counterparts. No differences in the frequency of monocyte subsets were found, although Angiotensin-Converting Enzyme expression was increased (non-classical: p<0.001; and intermediate: p<0.0001) in ISR. Despite no differences were noted in Low-Density Granulocytes, a relative increase in the CD16- compartment was observed in ISR (p=0.004). An unsupervised cluster analysis revealed the presence of three profiles with different clinical severity, unrelated to stent types or traditional risk factors. Conclusion: ISR is linked to excessive skin healing and profound alterations in cellular populations related to vascular repair and endothelial damage. Distinct cellular profiles can be distinguished within ISR, suggesting that different alterations may uncover different ISR clinical phenotypes.

Evaluation of a Rabbit Model of Vascular Stent Healing: Application of Optical Coherence Tomography.

Percutaneous coronary intervention (PCI) is a management strategy for symptomatic obstructive coronary artery disease (CAD). Despite advancements, in-stent restenosis (ISR) still imparts a 1-2% annual rate of repeat revascularization-a focus of ongoing translational research. Optical coherence tomography (OCT) provides high resolution virtual histology of stents. Our study evaluates the use of OCT for virtual histological assessment of stent healing in a rabbit aorta model, enabling complete assessment of intraluminal healing throughout the stent. ISR varies based on intra-stent location, stent length, and stent type in a rabbit model-important considerations for translational experimental design. Atherosclerosis leads to more prominent ISR proliferation independent of stent-related factors. The rabbit stent model mirrors clinical observations, while OCT-based virtual histology demonstrates utility for pre-clinical stent assessment. Pre-clinical models should incorporate clinical and stent factors as feasible to maximize translation to clinical practice.

Inflammatory Phenotype by OCT Coronary Imaging: Specific Features Among De Novo Lesions, In-Stent Neointima, and In-Stent Neo-Atherosclerosis. / Fenótipo Inflamatório por Imagem de OCT Coronária: Características Específicas Entre Lesões De Novo, Hiperplasia Intimal e Neoaterosclerose Intra-Stent.

BACKGROUND: Coronary stenosis can be caused de novo atherosclerosis, in-stent restenosis, and in-stent neoatherosclerosis, three entities that develop from a diverse pathophysiological milieu. OBJECTIVE: This study aims to investigate, using optical coherence tomography (OCT), whether or not coronary lesions related to these processes differ in their local inflammatory profile. METHODS: Retrospective analysis of patients with diagnosed or suspected coronary lesions who had undergone OCT imaging for clinical reasons. Macrophage and intra-plaque neovascularization were assessed by OCT and used as surrogates of local inflammation. A significance level of < 0.05 was adopted as statistically significant. RESULTS: From the 121 lesions, 74 were de novo, 29 were restenosis, and 18 were neoatherosclerosis. Neovascularization was found in 65.8% of de novo, 10.3% in restenosis, and 94.4% in neoatherosclerosis (p<0.01 for all). The volume of neovascularization was different among lesion types (950 vs. 0 vs. 6220, respectively [median values in 1000 x µm3/mm]; p<0.01 for all), which were significantly higher in neoatherosclerosis and lower in restenosis. The presence of macrophages differed among the lesions (95.9% in de novo vs. 6.9% in restenosis vs. 100% in neoatherosclerosis [p<0.01 for all]). Moreover, the intensity of macrophagic infiltration was different among lesion types (2.5 vs. 0.0 vs. 4.5, respectively [median values of macrophage score]; p<0.01 for all), significantly higher in neoatheroscleosis and lower in restenosis. CONCLUSION: When compared using coronary OCT, de novo atherosclerosis, in-stent restenosis, and neoatherosclerosis presented markedly different inflammatory phenotypes.

FUNDAMENTO: A estenose coronária pode ser causada por de novo aterosclerose, reestenose intra-stent e neoaterosclerose intra-stent, três entidades que se desenvolvem a partir de diversos meios fisiopatológicos. OBJETIVOS: Este estudo tem como objetivo investigar, por meio da tomografia de coerência óptica (OCT), se as lesões coronarianas relacionadas a esses processos diferem em seu perfil inflamatório local. MÉTODOS: Análise retrospectiva de pacientes com lesões coronárias diagnosticadas ou suspeitas que realizaram exames de OCT por motivos clínicos. Macrófagos e neovascularização intraplaca foram avaliados por OCT e utilizados como marcadores de inflamação local. O nível de significância < 0,05 foi adotado como estatisticamente significante. RESULTADOS: Das 121 lesões, 74 eram de novo , 29 eram reestenose e 18 eram neoaterosclerose. Neovascularização foi encontrada em 65,8% das de novo , 10,3% na reestenose e 94,4% na neoaterosclerose (p<0,01 para todos). O volume de neovascularização foi diferente entre os tipos de lesão (950 vs. 0 vs. 6.220, respectivamente [valores medianos em 1000 x µm 3 /mm]; p<0,01 para todos), sendo significativamente maior na neoaterosclerose e menor na reestenose. A presença de macrófagos diferiu entre as lesões (95,9% em de novo vs. 6,9% em reestenose vs. 100% em neoaterosclerose [p<0,01 para todos]). Além disso, a intensidade da infiltração macrofágica foi diferente entre os tipos de lesão (2,5 vs. 0,0 vs. 4,5, respectivamente [valores medianos do escore de macrófagos]; p<0,01 para todos), significativamente maior na neoaterosclerose e menor na reestenose. CONCLUSÕES: Quando comparados pela OCT coronariana, de novo , reestenose intra-stent e neoaterosclerose apresentaram fenótipos inflamatórios marcadamente diferentes.

A multiphysics modeling approach for in-stent restenosis: Theoretical aspects and finite element implementation.

Development of in silico models that capture progression of diseases in soft biological tissues are intrinsic in the validation of the hypothesized cellular and molecular mechanisms involved in the respective pathologies. In addition, they also aid in patient-specific adaptation of interventional procedures. In this regard, a fully-coupled high-fidelity Lagrangian finite element framework is proposed within this work which replicates the pathology of in-stent restenosis observed post stent implantation in a coronary artery. Advection-reaction-diffusion equations are set up to track the concentrations of the platelet-derived growth factor, the transforming growth factor-ß, the extracellular matrix, and the density of the smooth muscle cells. A continuum mechanical description of volumetric growth involved in the restenotic process, coupled to the evolution of the previously defined vessel wall constituents, is presented. Further, the finite element implementation of the model is discussed, and the behavior of the computational model is investigated via suitable numerical examples. Qualitative validation of the computational model is presented by emulating a stented artery. Patient-specific data are intended to be integrated into the model to predict the risk of in-stent restenosis, and thereby assist in the tuning of stent implantation parameters to mitigate the risk.

Prevalence, predictors, and outcomes of in-stent restenosis with calcified nodules.

BACKGROUND: Calcified nodules (CN) have been reported as being associated with stent failure including in-stent restenosis (ISR). However, there is no systematic study of this condition. AIMS: We aimed to clarify the prevalence, predictors, and midterm results of ISR lesions with CN. METHODS: We examined the clinical characteristics of 651 ISR lesions in patients who underwent percutaneous coronary intervention (PCI) with optical coherence tomography (OCT) between October 2008 and July 2016, and their 6- to 8-month follow-up angiography results. CN was defined as a high backscattering mass with small nodular calcium depositions which protruded into the vessel lumen. RESULTS: Thirty-two ISR lesions (4.9%) had CN. Multivariable analysis showed that calcified lesion (odds ratio [OR] 12.441, p<0.001), incomplete stent apposition (OR 3.228, p=0.005), haemodialysis (OR 3.633, p=0.024), and female gender (OR 3.212, p=0.036) were independently associated with ISR lesions with CN. Midterm follow-up was performed on 612 ISR lesions. Both ISR and target lesion revascularisation (TLR) rates were significantly higher in lesions with CN compared with those without CN (43.8% vs 25.0%, p=0.023; 37.5% vs 18.8%, p=0.020, respectively). However, multivariate analysis did not show the presence of CN as an independent predictor of re-TLR (OR 1.690, p=0.286). CONCLUSIONS: The prevalence of ISR lesions with CN was 4.9%. Calcified lesions, incomplete stent apposition, haemodialysis, and female gender are probably associated with CN formation. ISR lesions with CN may have poor midterm outcomes compared with ISR lesions without CN.

Ultrastructural Study of Platelet Behavior and Interrelationship in Sprouting and Intussusceptive Angiogenesis during Arterial Intimal Thickening Formation.

Platelets in atherosclerosis, bypass stenosis, and restenosis have been extensively assessed. However, a sequential ultrastructural study of platelets in angiogenesis during the early phases of these lesions has received less attention. Our objective was the study of platelets in angiogenesis and vessel regression during intimal thickening (IT) formation, a precursor process of these occlusive vascular diseases. For this purpose, we used an experimental model of rat occluded arteries and procedures for ultrastructural observation. The results show (a) the absence of platelet adhesion in the de-endothelialized occluded arterial segment isolated from the circulation, (b) that intraarterial myriad platelets contributed from neovessels originated by sprouting angiogenesis from the periarterial microvasculature, (c) the association of platelets with blood components (fibrin, neutrophils, macrophages, and eosinophils) and non-polarized endothelial cells (ECs) forming aggregates (spheroids) in the arterial lumen, (d) the establishment of peg-and-socket junctions between platelets and polarized Ecs during intussusceptive angiogenesis originated from the EC aggregates, with the initial formation of IT, and (e) the aggregation of platelets in regressing neovessels ('transitory paracrine organoid') and IT increases. In conclusion, in sprouting and intussusceptive angiogenesis and vessel regression during IT formation, we contribute sequential ultrastructural findings on platelet behavior and relationships, which can be the basis for further studies using other procedures.

Correlations between vitronectin, miR-520, and miR-34 in patients with stenosis of coronary arteries.

BACKGROUND: In-stent restenosis usually occurs by platelet activation, neointima formation, VSMC migration, and proliferation in the position of the vessel stent. The monocytes have a magnificent role in neointimal hyperplasia since these cells recruit to the site of vessel injury through chemokines and other secretion proteins. This study is focused on the investigation of vitronectin, miR-193, miR-34, and miR-520 expression levels in PBMCs isolated from stenosed patients. METHODS: A total of sixty subjects undergoing coronary artery angiography containing patients with stent no restenosis (n = 20), in-stent restenosis (n = 20), and healthy participants (n = 20) participated in the study. The vitronectin, miR-193, miR-34, and miR-520 expression levels were measured by the RT-qPCR technique. Data were analyzed by SPSS software. RESULTS: The vitronectin, miR-34, and miR-520 expression levels changed significantly in patients with vessel in-stent restenosis (p = 0.02, p = 0.02, and p = 0.01, respectively). Furthermore, there were inverse correlations between the expression levels of vitronectin gene and miR-34 (r = - 0.44, p = 0.04) as well as miR-520 (r = - 0.5, p=0.01). CONCLUSIONS: The molecular events in the vessel stenosis may be affected by targeting vitronectin with miR-520 and miR-34.

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.

Potential Mechanisms of In-stent Neointimal Atherosclerotic Plaque Formation.

ABSTRACT: Percutaneous coronary intervention has become the main revascularization strategy for coronary artery disease. Compared with early percutaneous coronary angioplasty and the extensive clinical application of bare metal stents, drug-eluting stents can significantly reduce the stenosis caused by the elastic retraction of plaque and neoatherosclerosis (NA), but there is still a high incidence of in-stent restenosis (ISR), which restricts the clinical efficacy of stent implantation. In-stent neoatherosclerosis (ISNA), defined as atherosclerotic lesions in the neointima, is one of the main causes of late stent failure. ISNA plays an important role in stent thrombosis and ISR. The rate of target lesion revascularization and in-stent thrombosis is high when NA arises. Therefore, it is of great clinical significance to explore the occurrence of NA and its development mechanism after stent implantation to prevent ISR and improve stent implantation efficacy and associated clinical prognosis. In this article, we systematically reviewed the existing clinical research on ISNA and the role of optical coherence tomography in its evaluation.

Melatonin attenuates restenosis after vascular injury in diabetic rats through activation of the Nrf2 signaling pathway.

Diabetes is a major risk factor for the development of cardiovascular disease. Diabetic patients have a higher incidence of restenosis following endovascular therapy than non-diabetic patients. Melatonin is primarily synthesized and secreted by the pineal gland and plays an important protective anti-inflammatory and antioxidant role in a variety of cardiovascular diseases. However, no studies to date have evaluated the underlying effects and molecular mechanisms of melatonin on diabetes-related restenosis. Herein, we used an in vivo model of diabetes-related restenosis and an in vitro model of high glucose-cultured vascular smooth muscle cells to investigate the anti-restenosis effect and signaling mechanisms induced by melatonin treatment. The present study provides the first evidence that melatonin attenuates restenosis following vascular injury in diabetic rats. We further investigated the underlying molecular mechanisms both in vivo and in vitro. The data suggest that the Nrf2 signaling pathway is an important molecular target for melatonin-mediated inhibition of diabetes-related restenosis after vascular injury. These findings indicate that melatonin may represent a potential candidate for the prevention or treatment of vascular diseases and restenosis following endovascular therapy, especially in diabetic patients.

Assessing the influence of atherosclerosis on drug coated balloon therapy using computational modelling.

Interventional therapies such as drug-eluting stents (DES) and drug-coated balloons (DCB) have significantly improved the clinical outcomes of patients with coronary occlusions in recent years. Despite this marked improvement, ischemic cardiovascular disease remains the most common cause of death worldwide. To address this, research efforts are focused on improving the safety and efficacy of the next generation of these devices. However, current experimental methods are unable to account for the influence of atherosclerotic lesions on drug uptake and retention. Therefore, in this study, we used an integrated approach utilizing both in vitro and in silico methods to assess the performance of DCB therapy. This approach was validated against existing in vivo results before being used to numerically estimate the effect of the atheroma. A bolus release of sirolimus was observed with our coating matrix. This, coupled with the rapid saturation of specific and non-specific binding sites observed in our study, indicated that increasing the therapeutic dose coated onto the balloons might not necessarily result in greater uptake and/or retention. Additionally, our findings alluded to an optimal exposure time, dependent on the coating matrix, for the DCBs to be expanded against the vessel. Moreover, our findings suggest that a biphasic drug release profile might be beneficial for establishing and maintaining the saturation of bindings sites within severely occluded vessels. Ultimately, we have demonstrated that computational methods may be capable of assessing the efficacy of DCB therapy as well as predict the influence of atherosclerotic lesions on said efficacy.

H2S attenuates oxidative stress via Nrf2/NF-κB signaling to regulate restenosis after percutaneous transluminal angioplasty.

Restenosis after angioplasty of peripheral arteries is a clinical problem involving oxidative stress. Hydrogen sulfide (H2S) participates in oxidative stress regulation and activates nuclear factor erythroid 2-related factor 2 (Nrf2). This study investigated the effect of H2S and Nrf2 on restenosis-induced arterial injury. Using an in vivo rat model of restenosis, we investigated whether H2S inhibits restenosis after percutaneous transluminal angioplasty (PTA) and the oxidative stress-related mechanisms implicated therein. The involvement of Nrf2 was explored using Nrf2-shRNA. Neointimal formation and the deposition of elastic fibers were assessed histologically. Inflammatory cytokine secretion and the expression of proteins associated with oxidative stress and inflammation were evaluated. The artery of rats subjected to restenosis showed increased arterial intimal thickness, with prominent elastic fiber deposition. Sodium hydrosulfide (NaHS), an H2S donor, counteracted these changes in vivo. Restenosis caused a decrease in anti-oxidative stress signaling. This phenomenon was inhibited by NaHS, but Nrf2-shRNA counteracted the effects of NaHS. In terms of inflammation, inflammatory cytokines were upregulated, whereas NaHS suppressed the induced inflammatory reaction. Similarly, Nrf2 downregulation blocked the effect of NaHS. In vitro studies using aortic endothelial and vascular smooth muscle cells isolated from experimental animals showed consistent results as those of in vivo studies, and the participation of the nuclear factor-kappa B signaling pathway was demonstrated. Collectively, H2S played a role in regulating post-PTA restenosis by alleviating oxidative stress, modulating anti-oxidant defense, and targeting Nrf2-related pathways via nuclear factor-kappa B signaling.