Ruxolitinib attenuates intimal hyperplasia via inhibiting JAK2/STAT3 signaling pathway activation induced by PDGF-BB in vascular smooth muscle cells.

BACKGROUND: Cardiovascular diseases are associated with proliferation and phenotypic switch. Platelet-derived growth factor-BB (PDGF-BB) is a major initiating factor for proliferative vascular diseases, such as neointimal lesion formation, restenosis after angioplasty, and atherosclerosis. Ruxolitinib, a potent Janus kinase (JAK) 1 and 2 inhibitor, has been reported to significantly block the proliferation-related signaling pathway of JAK2/signal transducers and activators of transcription 3 (STAT3) and harbor a broad spectrum of anti-cancer activities, including proliferation inhibition, apoptosis induction, and anti-inflammation. However, the role of ruxolitinib in regulating PDGF-BB-induced VSMC proliferation remains to be elucidated. Thus, this study investigates the role of ruxolitinib in regulating PDGF-BB-induced VSMC proliferation and its underlying mechanisms. METHODS: In vivo, the medial thickness of the carotid artery was evaluated using a mouse carotid ligation model, ruxolitinib was administered orally to the mice every other day, and the mice were euthanized on day 28 to evaluate the therapeutic effects of ruxolitinib. Cell proliferation markers were measured using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. In vitro, VSMCs were treated with ruxolitinib with or without PDGF-BB at an indicated time and concentration. Cell proliferation and apoptosis were measured using Cell Counting Kit-8 assay, MTS assays and flow cytometry. The JAK2/STAT3 signaling pathway involved in the effects of ruxolitinib on VSMCs was detected by western blotting with the specific pathway inhibitor AG490. RESULTS: In vivo, ruxolitinib significantly decreased the ratio-of-intima ratio (I/M ratio) by inhibiting the expression of PCNA and cyclinD1 (p <0.05). In vitro, ruxolitinib inhibited PDGF-BB-induced VSMC proliferation compared with the PDGF-BB treatment group (p <0.05). In addition, ruxolitinib inhibited the PDGF-BB-induced activation of the JAK2/STAT3 signaling pathway and decreased the expression of proliferation related-proteins cyclinD1 and PCNA in VSMCs (p <0.05). CONCLUSION: Our findings suggest that ruxolitinib inhibits VSMC proliferation in vivo and in vitro by suppressing the activation of the JAK2/STAT3 signaling pathway. Therefore, ruxolitinib has a therapeutic potential for proliferative vascular diseases.

Medical prevention and treatment of radiation-induced carotid injury.

Radiotherapy has significantly improved the survival of cancer patients but is also associated with several adversities, including radiation-induced carotid injury (RICI). The RICI mechanisms are complex, including vessel inflammatory injury, carotid atherosclerosis, intimal proliferation, media necrosis, and peri-adventitial fibrosis. The main manifestation and adverse consequence of RICI is carotid artery stenosis (CAS), which can lead to stroke and transient ischemic attack. Currently, carotid artery injury is primarily diagnosed via color-coded duplex sonography. Early detection of traumatic changes in the carotid artery depends on measurements of carotid intima-media thickness; serum biomarker testing also shows great potential. CAS is mainly treated with carotid endarterectomy or carotid angioplasty and stent implantation. Notably, bone marrow mesenchymal stem cells are advantageous in RICI treatment and reduce carotid inflammation, oxidative stress, and delaying atherosclerosis. This review summarizes the mechanisms, examination methods, and latest treatments for RICI to provide data for its clinical prevention and treatment.

Inhibition of miR-223 Expression Using a Sponge Strategy Decreases Restenosis in Rat Injured Carotids.

OBJECTIVE: Restenosis is a frequent complication of angioplasty. It consists of a neointimal hyperplasia resulting from progression and migration of vascular smooth muscle cells (VSMC) into the vessel lumen. microRNA miR-223 has recently been shown to be involved in cardiovascular diseases including atherosclerosis, vascular calcification and arterial thrombosis. In this study, our aim was to assess the impact of miR-223 modulation on restenosis in a rat model of carotid artery after balloon injury. METHODS: The over and down-expression of miR-223 was induced by adenoviral vectors, containing either a pre-miR-223 sequence allowing artificial miR-223 expression or a sponge sequence, trapping the native microRNA, respectively. Restenosis was quantified on stained rat carotid sections. RESULTS: In vitro, three mRNA (Myocyte Enhancer Factor 2C (MEF2C), Ras homolog gene family, member B (RhoB) and Nuclear factor 1 A-type (NFIA)) reported as miR-223 direct targets and known to be implicated in VSMC differentiation and contractility were studied by RT-qPCR. Our findings showed that down-expression of miR-223 significantly reduced neointimal hyperplasia by 44% in carotids, and was associated with a 2-3-fold overexpression of MEF2C, RhoB and NFIA in a murine monocyte macrophage cell line, RAW 264.7 cells. CONCLUSION: Down-regulating miR-223 could be a potential therapeutic approach to prevent restenosis after angioplasty.

Prevention of Vascular Anastomotic Stenosis With 2-Octylcyanoacrylate.

Although conventional microvascular anastomoses are well-studied, postoperative anastomotic stenoses remain a common surgical complication. The use of 2-octylcyanoacrylate to stabilize vascular anastomoses using a rabbit anastomosis model was investigated. A carotid artery anastomosis model was established in 20 New Zealand rabbits (2.5-3.0 kg): 10 underwent conventional anastomosis surgery with sutures only, while 10 underwent suture ligation, followed by the application of 2-octylcyanoacrylate. Vascular patency and pulse strength were observed after adhesive solidification. The artery diameter was measured preoperatively and at 5 minutes, 2 weeks, and 4 weeks postoperatively. An angiography was performed at 4 weeks postoperatively. Hyperplasia and the induced nitric oxide synthase (iNOS) content of the intima and media layers from the anastomotic stoma were assessed using immunohistochemistry. The artery inner diameter of experimental group decreased at each time point postoperatively (1.686 ±â€Š0.066 cm; 1.656 ±â€Š0.069 cm; 1.646 ±â€Š0.074 cm) (P ≤ 0.01). At 4 weeks postoperatively, the intima and the media around the anastomosis was both significantly thinner in the experimental group (13.21 ±â€Š0.84 µm; 234.86 ±â€Š13.84 µm) than in the control group (17.06 ±â€Š0.96 µm; 279.88 ±â€Š34.22 µm) (P < 0.05). At 4 weeks postsurgery, intravascular iNOS expression was increased in both groups but was higher in the experimental group (82.5% versus 47.5%). The above results indicated that 2-octylcyanoacrylate adhesive can inhibit stenosis of vascular anastomoses.

Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017.

The 2017 update of The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke is a collection of current evidence-based recommendations intended for use by clinicians across a wide range of settings. The goal is to provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations include those related to diagnostic testing, diet and lifestyle, smoking, hypertension, hyperlipidemia, diabetes, antiplatelet and anticoagulant therapies, carotid artery disease, atrial fibrillation, and other cardiac conditions. Notable changes in this sixth edition include the development of core elements for delivering secondary stroke prevention services, the addition of a section on cervical artery dissection, new recommendations regarding the management of patent foramen ovale, and the removal of the recommendations on management of sleep apnea. The Canadian Stroke Best Practice Recommendations include a range of supporting materials such as implementation resources to facilitate the adoption of evidence to practice, and related performance measures to enable monitoring of uptake and effectiveness of the recommendations. The guidelines further emphasize the need for a systems approach to stroke care, involving an interprofessional team, with access to specialists regardless of patient location, and the need to overcome geographic barriers to ensure equity in access within a universal health care system.

[Severe Carotid Artery Disease;Preoperative Assessment and Perioperative Management].

Cerebrovascular complication is the one of the most dreadful complication after open heart surgery which leads to significant decrease of quality of life even if the patients survived. To decrease these complications, carotid doppler echo as one of the non-invasive carotid screening modalities is effective. Carotid artery stenosis is common in the patients with coronary artery disease, and it is more frequent in the patients with more complexed coronary artery lesions. The more the patients indicated for coronary artery bypass grafting has complexed lesions these days, the more the patients have carotid artery lesions. In case of presence of significant carotid artery stenosis with symptom, carotid artery intervention, either carotid endarterectomy or carotid artery stenting, should be considered by multidisciplinary team. The carotid artery stenosis could cause cerebral infarction by 2 major mechanisms, which are emboli, and low perfusion pressure. In open heart surgery, it is very important to avoid these occasions. Although It is still controversial whether off-pump coronary artery bypass grafting is superior to conventional on-pump coronary artery bypass grafting in randomized trial, it is necessary in common to avoid atheromatous emboli from aorta and to avoid low perfusion pressure by all means.

Incretin treatment and atherosclerotic plaque stability: Role of adiponectin/APPL1 signaling pathway.

AIMS: Glucagon like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPP-4) inhibitors reduce atherosclerosis progression in type 2 diabetes mellitus (T2DM) patients and are associated with morphological and compositional characteristics of stable plaque phenotype. GLP-1 promotes the secretion of adiponectin which exerts anti-inflammatory effects through the adaptor protein PH domain and leucine zipper containing 1 (APPL1). The potential role of APPL1 expression in the evolution of atherosclerotic plaque in TDM2 patients has not previously evaluated. METHODS: The effect of incretin therapy in the regulation of adiponectin/APPL1 signaling was evaluated both on carotid plaques of asymptomatic diabetic (n=71) and non-diabetic patients (n=52), and through in vitro experiments on endothelial cell (EC). RESULTS: Atherosclerotic plaques of T2DM patients showed lower adiponectin and APPL1 levels compared with non-diabetic patients, along with higher oxidative stress, tumor necrosis factor-α (TNF-α), vimentin, and matrix metalloproteinase-9 (MMP-9) levels. Among T2DM subjects, current incretin-users presented higher APPL1 and adiponectin content compared with never incretin-users. Similarly, in vitro observations on endothelial cells co-treated with high-glucose (25mM) and GLP-1 (100nM) showed a greater APPL1 protein expression compared with high-glucose treatment alone. CONCLUSIONS: Our findings suggest a potential role of adiponectin/APPL1 signaling in mediating the effect of incretin in the prevention of atherosclerosis progression or plaque vulnerability in T2DM.

Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice.

Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE-/- carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.

Alkaloid rich fraction from Nelumbo nucifera targets VSMC proliferation and migration to suppress restenosis in balloon-injured rat carotid artery.

AIMS: Restenosis- an adverse consequence following angioplasty, and atherosclerosis are characterized by abnormal vascular smooth muscle cell (VSMC) proliferation and migration leading to neo-intima formation. In the present study, we investigated the inhibitory effects of alkaloid rich fraction (ARF) from Nelumbo nucifera and isolated compound neferine on platelet-derived growth factor (PDGF-BB) induced VSMC proliferation and migration in vitro and neo-intima formation in a rat carotid artery injury model. METHODS: PDGF-BB induced VSMC proliferation and migration was assessed using colorimetric assay and modified Boyden chamber method respectively. Gene expression of cell cycle associated molecules was determined by reverse transcription-polymerase chain reaction (RT-PCR). The signaling molecules such as PDGF-Rß, extracellular regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), P38, metalloproteinase (MMP)-9 and nuclear factor-kappa B (NF-κB) were determined by western blot analysis. Stress fiber formation was evaluated using immunofluorescence microscopy. The rat carotid artery balloon injury model was performed to assess the effect of ARF on neo-intima formation. RESULTS: ARF possessed the strongest anti-oxidant activities. The anti-proliferative activity of both ARF and neferine was due to suppression of cyclin D1, cyclin E and cyclin-dependent kinase (Cdk) gene expression. Moreover, ARF and neferine inhibited PDGF-Rß, ERK1/2, JNK and P38 activations and NF-κB translocation. Also, ARF and neferine inhibited VSMC migration by inhibiting MMP-9 activity without affecting cytoskeleton remodeling. In a rat carotid artery injury model, ARF inhibited neo-intima formation. CONCLUSION: Our results indicate that ARF targets VSMC proliferation and migration to attenuate neo-intima formation by inhibition of PDGF-Rß mediated signaling.

The ubiquitin-activating enzyme E1 as a novel therapeutic target for the treatment of restenosis.

AIMS: The ubiquitin-activating enzyme E1 (UBA1, E1), the apex of the ubiquitin proteasome pathway, plays a critical role in protein degradation and in pathological processes. Whether UBA1 participates the development of vascular restenosis remains unknown. This study aims to determine the role of UBA1 in the development of balloon injury induced neointimal formation. METHODS AND RESULTS: Immunostaining and western blots were used to examine the expression of the ubiquitinated protein in the injured carotid after angioplasty. Higher levels of ubiquitinated protein were observed in the neointima. Local delivery of potent chemical UBA1 inhibitor PYR-41 (100 µM) and UBA1 shRNA lentivirus both resulted in a substantial decrease in intimal hyperplasia at 2 weeks and 4 weeks after balloon injury. UBA1 inhibition also reduced Ki-67 positive cell percentage and inflammatory response in the carotid artery wall. We further determined that in vitro UBA1 inhibition was able to ameliorate TNF-α-induced nuclear factor-kappa B (NF-κB) activation by reducing IκB degradation in vascular smooth muscle cells (VSMCs). UBA1 inhibition also led to the accumulation of short-lived proteins such as p53, p21 and c-jun, which may account for the UBA1 inhibition-induced cell cycle delay. Thus, VSMCs proliferation was blocked. CONCLUSIONS: UBA1 inhibition effectively suppresses neointimal thickening through its anti-proliferative and anti-inflammatory effects. Our results provide further evidence that the ubiquitin-proteasome system is a potential new target for the prevention of vascular restenosis.

Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells.

OBJECTIVE: Thrombomodulin is highly expressed on the lumenal surface of vascular endothelial cells (ECs) and possesses potent anticoagulant, antifibrinolytic, and anti-inflammatory activities in the vessel wall. However, the regulation of thrombomodulin expression in ECs remains largely unknown. APPROACHES AND RESULTS: In this study, we characterized nuclear receptor 4A family as a novel regulator of thrombomodulin expression in vascular ECs. We demonstrated that both nuclear receptors 4A, Nur77 and Nor1, robustly increase thrombomodulin mRNA and protein levels in human vascular ECs and in mouse liver tissues after adenovirus-mediated transduction of Nur77 and Nor1 cDNAs. Moreover, Nur77 deficiency and knockdown of Nur77 and Nor1 expression markedly attenuated the basal and vascular endothelial growth factor165-stimulated thrombomodulin expression. Mechanistically, we found that Nur77 and Nor1 increase thrombomodulin expression by acting through 2 different mechanisms. We showed that Nur77 barely affects thrombomodulin promoter activity, but significantly increases thrombomodulin mRNA stability, whereas Nor1 enhances thrombomodulin expression mainly through induction of Kruppel-like factors 2 and 4 in vascular ECs. Furthermore, we demonstrated that both Nur77 and Nor1 significantly increase protein C activity and inhibit tumor necrosis factor α-induced prothrombotic effects in human ECs. Deficiency of Nur77 increases susceptibility to arterial thrombosis, whereas enhanced expression of Nur77 and Nor1 protects mice from arterial thrombus formation. CONCLUSIONS: Our results identified nuclear receptors 4A as novel regulators of thrombomodulin expression and function in vascular ECs and provided a proof-of-concept demonstration that targeted increasing expression of Nur77 and Nor1 in the vascular endothelium might represent a novel therapeutic approach for the treatment of thrombotic disorders.

Human urine kininogenase attenuates balloon-induced intimal hyperplasia in rabbit carotid artery through transforming growth factor ß1/Smad2/3 signaling pathway.

OBJECTIVE: Effective treatments against restenosis after percutaneous transluminal angioplasty and stenting are largely lacking. Human tissue kallikrein gene transfer has been shown to be able to attenuate neointima formation induced by balloon catheter. As a tissue kallikrein in vivo, human urinary kininogenase (HUK) is widely used to prevent ischemia-reperfusion injury. However, the effects of HUK on neointima formation have not been explored. We therefore investigated whether HUK could alleviate balloon catheter-induced intimal hyperplasia in rabbits fed with high-fat diets. METHODS: The effects of HUK on neointima and atherosclerosis formation were analyzed by hematoxylin-eosin staining and immunohistochemical staining in balloon-injured carotid arteries of rabbits. Local inflammatory response was evaluated by detecting the gene expression of tumor necrosis factor α and interleukin 1ß with real-time quantitative polymerase chain reaction plus the invasion of macrophages with immunohistochemical staining. Western blotting was employed to investigate the effects of HUK on activities of endothelial nitric oxide synthase (eNOS), transforming growth factor ß1 (TGF-ß1), and Smad signaling pathway. The long-term effect of HUK on intimal hyperplasia of the injured carotid artery was assessed by angiography. RESULTS: Quantitative image analysis showed that intravenous administration of HUK for 14 days significantly decreased the intimal areas and intima area/media area ratios (day 14, 54% decrease in intimal area and 58% decrease in intima area/media area ratios; day 28, 63% and 85%). Significant decreases were also noted in macrophage foam cell-positive area after 7-day or 14-day administration of HUK (day 7, 69% decrease in intimal area and 78% decrease in media area; day 14, 79% and 60%; day 28, 68% and 44%). Actin staining for smooth muscle cells in neointima at 2 months showed similar results (vascular smooth muscle cell-positive area of neointima, 28.21% ± 5.58% vs 43.78% ± 8.36%; P < .05). Real-time quantitative polymerase chain reaction or Western blot analysis showed that HUK reduced expression of tumor necrosis factor α, interleukin 1ß, TGF-ß1, and p-Smad2/3 but increased the expression of p-eNOS. Angiography analysis showed that 14-day administration of HUK significantly decreased the degree of stenosis (26.8% ± 7.1% vs 47.9% ± 5.7%; P < .01) at 2 months after balloon injury. CONCLUSIONS: Our results indicate that HUK is able to attenuate atherosclerosis formation and to inhibit intimal hyperplasia by downregulating TGF-ß1 expression and Smad2/3 phosphorylation, upregulating eNOS activity. HUK may be a potential therapeutic agent to prevent stenosis after vascular injury.

[Asymptomatic carotid artery stenosis--is screening useful?]. / Asymptomatische Carotisstenose--wie sinnvoll ist Screening?

Stenoses of the carotid artery are associated with an increased stroke risk. Duplex ultrasound is the method of choice for screening for carotid artery stenosis. Unselected screening for carotid stenosis in unselected persons is not efficient and cannot be recommended. Screening by vascular ultrasound, however, is indicated in patients with neurologic symptoms from cerebral territories supplied by the anterior or mid cerebral artery, and in asymptomatic patients with carotid bruits, atherosclerotic disease in other vascular territories, after contralateral carotid artery revascularization, and after radiation therapy of the neck.

Catching up on the latest USPSTF recommendations.

Screening is now encouraged for hepatitis B in those at high risk and for gestational diabetes at 24 weeks gestation. Low-dose aspirin is also advised for pregnant women at risk for preeclampsia.

Association between physical activity and peripheral artery disease and carotid artery stenosis in a self-referred population of 3 million adults.

OBJECTIVE: Although the relationship between physical activity and coronary heart disease is well characterized, a paucity of data exists on physical activity and vascular disease in other arterial territories. This study examined the prevalence of peripheral artery disease (PAD) and carotid artery stenosis (CAS) in association with physical activity. APPROACH AND RESULTS: The association between physical activity and vascular disease was examined in >3 million self-referred US participants in the United States from 2003 to 2008 who completed a medical and lifestyle questionnaire in the Life Line screening program. All subjects were evaluated by screening ankle brachial indices <0.90 for PAD and ultrasound imaging for CAS >50%. Multivariable logistic regression modeling was used to estimate odds of disease. Among 3 250 350 subjects, 63% of the population engaged in some leisure time vigorous physical activity. After adjustment for age, sex, race/ethnicity, hypertension, hypercholesterolemia, smoking status, diabetes mellitus, body mass index, and family history of cardiovascular disease, subjects who reported any physical activity had a significantly lower odds of PAD (odds ratio, 0.64; 95% confidence interval, 0.63-0.65) and CAS (odds ratio, 0.80; 95% confidence interval, 0.79-0.81). The association between physical activity with PAD and CAS was robust when stratified by sex, race, and age categories. Physical activity intensity frequency was associated with lower PAD and CAS in a graded manner (P trend <0.0001 for both). Findings seemed unaffected by confounding by comorbidity or indication. CONCLUSIONS: In a large population-based study, higher levels of physical activity were independently associated with lower odds of vascular disease in the lower extremities and carotid arteries.

Anti-inflammatory immune skewing is atheroprotective: Apoe−/−FcγRIIb−/− mice develop fibrous carotid plaques.

BACKGROUND: Stroke, caused by carotid plaque rupture, is a major cause of death in the United States. Whereas vulnerable human plaques have higher Fc receptor (FcγR) expression than their stable counterparts, how FcγR expression impacts plaque histology is unknown. We investigated the role of FcγRIIb in carotid plaque development and stability in apolipoprotein (Apo)e−/− and Apoe−/−FcγRIIb−/− double knockout (DKO) animals. METHODS AND RESULTS: Plaques were induced by implantation of a shear stress­modifying cast around the carotid artery. Plaque length and stenosis were followed longitudinally using ultrasound biomicroscopy. Immune status was determined by flow cytometry, cytokine release, immunoglobulin G concentration and analysis of macrophage polarization both in plaques and in vitro. Surprisingly, DKO animals had lower plaque burden in both carotid artery and descending aorta. Plaques from Apoe−/− mice were foam­cell rich and resembled vulnerable human specimens, whereas those from DKO mice were fibrous and histologically stable. Plaques from DKO animals expressed higher arginase 1 (Arg­1) and lower inducible nitric oxide synthase (iNOS), indicating the presence of M2 macrophages. Analysis of blood and cervical lymph nodes revealed higher interleukin (IL)­10, immune complexes, and regulatory T cells (Tregs) and lower IL­12, IL­1ß, and tumor necrosis factor alpha (TNF­α) in DKO mice. Similarly, in vitro stimulation produced higher IL­10 and Arg­1 and lower iNOS, IL­1ß, and TNF­α in DKO versus Apoe−/− macrophages. These results define a systemic anti­inflammatory phenotype. CONCLUSIONS: We hypothesized that removal of FcγRIIb would exacerbate atherosclerosis and generate unstable plaques. However, we found that deletion of FcγRIIb on a congenic C57BL/6 background induces an anti­inflammatory Treg/M2 polarization that is atheroprotective.

Protective effect of melatonin on cigarette smoke-induced restenosis in rat carotid arteries after balloon injury.

Vascular restenosis after the interventional angioplasty remains the main obstacle to a favorable long-term patency. Many researches suggest cigarette smoking is one of the most important causes of restenosis. This study was designed to investigate whether melatonin could protect against the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury. Three groups of male rats (normal condition, cigarette smoke exposed, cigarette smoke exposed, and melatonin injected) were used in this study. An established balloon-induced carotid artery injury was performed, and the carotid arteries were harvested from these three groups 14 days later. The ratio of intima to media, the infiltration of inflammatory cells, the expression of inflammatory cytokines (NF-κB, IL-1ß, IL-6, TNF-α, MCP-1), adhesion molecules (ICAM-1, VCAM-1), and eNOS were measured. The results showed that cigarette smoke exposure aggravated the stenosis of the lumen, promoted the infiltration of inflammatory cells and induced the expression of the inflammatory cytokines and adhesion molecules after the balloon-induced carotid artery injury. Moreover, cigarette smoke exposure can inhibit the expression of eNOS. Particularly, we surprised that melatonin could minimize this effect caused by cigarette smoke. These results suggested that melatonin could prevent the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury and the mechanism of its protective effect may be the inhibition of the inflammatory reaction. This also implies melatonin has the potential therapeutic applicability in prevention of restenosis after the vascular angioplasty in smokers.

Stylocarotid artery syndrome.

Stylocarotid artery syndrome is a rare condition that results from compression of the internal or external carotid artery by the styloid process of the temporal bone. Here we present the case of a patient suffering from syncope, monoparesis of the right arm, and dysarthria due to recurrent transient ischemic attacks that resulted from severe compression of the midsegment of the left extracranial internal carotid artery between an elongated styloid process and a C2 vertebral body osteophyte. This case demonstrates successful surgical management of a condition rarely encountered by the vascular surgeon.