Multiple Cerebrovascular Insults in Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is a rare systemic genetic disorder and an uncommon cause of ischaemic and haemorrhagic strokes. Its rarity and variable presentation may delay recognition and diagnosis of the primary disorder or associated conditions. Here, we describe a patient of European ancestry diagnosed with PXE in her 20s who presented in her 50s with a haemorrhagic stroke. Subsequent workup additionally revealed clinically silent ischaemic cerebral infarcts, critical stenosis of the right internal carotid artery and intracranial vasculopathy. Though she had some typical vascular risk factors, they were well-controlled. Antiplatelet therapy has traditionally been avoided in PXE due to increased risk of GI (and potentially retinal and cerebral) haemorrhage, but the medical team opted to start aspirin for secondary stroke prevention because she had no history of GI or retinal bleed, and her risk of ischaemic stroke was considered unacceptably high compared with that of clinically significant haemorrhage. Judicious use of antiplatelet therapy may be relatively safe in carefully selected patients. Anticipatory surveillance and management of the numerous manifestations of this potentially debilitating disorder are also important to preserve function and quality of life.

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.

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.

Carotid Stent Restenosis and Thrombosis in Rabbits: The Effect of Antiplatelet Agents.

BACKGROUND: The purpose of the study was the comparative assessment of ticagrelor and clopidogrel effects on carotid post-balloon injury (PBI) and on post carotid artery stenting (CAS) rate of in-stent restenosis (ISR) and in-stent thrombosis in atherosclerotic rabbits. METHODS: Forty-eight New Zealand white rabbits on high-fat diet were randomized into 4 groups: A1: PBI and clopidogrel (30 mg/kg/d), A2: PBI and ticagrelor (21 mg/kg twice daily), B1: PBI, CAS, and clopidogrel (30 mg/kg/d), B2: PBI, CAS, and ticagrelor (21 mg/kg twice daily). All rabbits received orally aspirin (10 mg/kg/d) and interventions were performed in their right carotid arteries (RCAs). Optical coherence tomography (OCT) and carotid angiography were performed at end point, while platelet aggregation and lipid profile were measured. After euthanasia both carotids were obtained for histological examination. RESULTS: In B1 group, 3 rabbits presented thrombotic total occlusion of the stents, while none such episode was observed in B2 group. The neointimal areas in RCAs, calculated by OCT, did not differ between A1 and A2 groups, and between B1 and B2 groups (P > .05). From the histological findings, the intima/(media + intima) percentage (%) in RCAs of balloon-injured rabbits did not present any difference between groups (P = .812). Similarly, the immunohistochemically determined accumulation of endothelial cells and macrophages on vascular walls was equivalent between groups (P > .05). CONCLUSION: Following carotid balloon injury and stenting, clopidogrel and ticagrelor did not show any differential effects on the extent of neointimal formation and ISR in atherosclerotic rabbits receiving aspirin. Three thrombotic stent occlusions were noted in the clopidogrel treatment group, but this finding was not statistically significant.

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.

Drug-Eluting Stent Targeting Sp-1-Attenuated Restenosis by Engaging YAP-Mediated Vascular Smooth Muscle Cell Phenotypic Modulation.

Background Activation of the YAP (Yes-associated protein) pathway has been demonstrated to be related to smooth muscle cells (SMCs) phenotypic modulation and vessel restenosis. The aim of this study was to illustrate the molecular mechanisms that regulate the expression of YAP during the process of SMCs phenotypic switch. Whether the molecular basis identified in the study could be a potential therapeutic target for drug-eluting stents is further tested. Methods and Results In cell culture and in rat carotid arterial injury models, Sp-1 (specificity protein 1) expression was significantly induced, and correlated with SMCs proliferative phenotype. Overexpression of Sp-1 promoted SMCs proliferation and migration. Conversely, siSp-1 transfection or Sp-1 inhibitor Mithramycin A treatment attenuates SMC proliferation and migration. Through gain- and loss-function assays, we demonstrated that YAP was involved in Sp-1-mediated SMC phenotypic switch. Mechanistically, activated Sp-1 regulated YAP transcriptional expression through binding to its promoter. Moreover, we fabricated a Sp-1 inhibitor Mithramycin A-eluting stent and further tested it. In the rabbit carotid model, Mithramycin A-eluting stent inhibited YAP transcription and attenuated in-stent restenosis through regulating YAP-mediated SMC phenotypic switch. Conclusions Sp-1 controls phenotypic modulation of SMC by regulating transcription factor YAP. Drug-eluting stent targeting Sp-1 might represent a novel therapeutic strategy to prevent in-stent restenosis.

Carotid Atherosclerosis in Patients with Atrial Fibrillation.

PURPOSE OF REVIEW: This review aims to explore the relationship between AF and carotid atherosclerosis, and the impact on the outcomes of cardiovascular and cerebrovascular events. Also, our aim is to critically review current knowledge and delineate future directions for effective treatment or prevention as well as strategies for improvement of the quality of life and survival. RECENT FINDINGS: Atrial fibrillation (AF) is the most common arrhythmia, increasing the risk of stroke and cardiovascular morbidity and mortality representing a significant worldwide public health problem. On the other hand, carotid artery atherosclerosis can also significantly increase the risk of stroke, transient ischemic attack (TIA), and death. Firstly, we report epidemiological data on AF patients in different countries and regions having carotid artery abnormalities such as carotid artery plaque formation, atherosclerotic, and even stenosis. Despite geographical variations, these abnormalities were more frequent in AF patients and correlated with the duration of AF and the value of CHA2DS2-VASc score. Moreover, it is evident that AF patients with carotid artery abnormalities have significantly increased risk of adverse outcomes from the heart and brain. According to the CHA(2)DS2 (-VASc) score, AF patients are managed with anticoagulation therapy. Reviewing existing data on the treatment for stroke prevention in patients with AF, carotid artery disease, or both, we found that antiplatelet therapy could be combined with anticoagulant therapy appropriately in certain circumstances. In addition, some emerging technologies, such as the percutaneous permanent carotid filter, may be used safely and effectively to prevent the occurrence of stroke in patients both with AF and carotid artery atherosclerosis.

Lifestyle Interventions and Carotid Plaque Burden: A Comparative Analysis of Two Lifestyle Intervention Programs in Patients with Coronary Artery Disease.

BACKGROUND: The cardioprotective effects of intensive lifestyle regimens in primary prevention have been elucidated; however, there is a paucity of data comparing the effects of different lifestyle regimens in patients with established coronary artery disease (CAD) or CAD equivalent, specifically vis-à-vis carotid plaque regression. METHODS: We performed a randomized, single-center, single-blind study in 120 patients with established CAD. Patients were randomly assigned to either 9 months of the Complete Health Improvement Program (CHIP), an outpatient lifestyle enrichment program that focuses on improving dietary choices, enhancing daily exercise, increasing support systems, and decreasing stress; or to 9 months of an ad hoc, nonsequential combination of various healthy living classes offered separately through a health maintenance organization and referred to as the Healthy Heart program. Baseline and 9-month change in carotid intima-media thickness (CIMT) were measured. RESULTS: Among 120 participants, data were analyzed for 79, of which 68 (86%) completed the study. Both average CIMT and average maximum CIMT increased over 9 months, but the changes between groups were insignificant. There were marked differences in the mean body mass index favoring the CHIP group (-1.9 [standard deviation = 1.9]; p < 0.001) and statistically significant within-group improvements in blood pressure, triglyceride level, 6-minute walk test result, self-assessment well-being score, and Patient Health Questionnaire-9 score that were not observed between groups. CONCLUSION: Neither the CHIP nor Healthy Heart was effective in inducing plaque regression in patients with established CAD after a 9-month period. However, both were effective in improving several CAD risk factors, which shows that the nonsequential offering of healthy lifestyle programs can lead to similar outcomes as a formal, sequential, established program (CHIP) in many aspects. These results have important implications as to how lifestyle changes will be implemented as tertiary prevention measures in the future.

Carotid artery stenting: an update.

PURPOSE OF REVIEW: To present the latest evidence about carotid artery stenting (CAS) including indications, safety, efficacy, and available equipment. RECENT FINDINGS: The micromesh stent, a new stent design which offers excellent flexibility and embolic protection, has been associated with promising outcomes. SUMMARY: CAS has emerged as a minimally invasive treatment method for carotid artery stenosis with comparable outcomes with surgical management. The implementation of new technology combined with operator experience has led to a paradigm shift; however, to date, no robust evidence exists about patient and lesion selection. Many studies are underway to clarify the technical aspects of CAS as well as the optimal treatment of carotid artery stenosis for each patient population.

Drug-eluting stent specifically designed to target vascular smooth muscle cell phenotypic modulation attenuated restenosis through the YAP pathway.

Vascular smooth muscle cell (SMC) phenotypic modulation contributes to the development of restenosis. A sorafenib-eluting stent was specifically designed to target SMC phenotypic modulation to inhibit in-stent restenosis in the present study. SMC contractile protein from the freshly isolated rat aorta was expressed at a high level, but its expression was dramatically reduced after SMCs were cultured in 10% FBS for 1 wk. After sorafenib treatment, SMC contractile protein expression was markedly upregulated. We further observed that Yes-associated protein (YAP) expression was attenuated after sorafenib treatment in a dose-dependent manner. Overexpression of YAP by lentivirus reversed the expression of sorafenib-induced SMC contractile protein and increased the expression of cyclin D. Mechanistically, sorafenib regulated the serum response factor-myocardin (SRF-Myocd) complex through competitive binding of YAP to Myocd and increased SRF binding to CArG-containing regions of SMC-specific contractile genes within intact chromatin, thereby controlling the activity of smooth muscle-specific gene transcription. In a rabbit carotid model, the sorafenib-eluting stent (SFES) dramatically inhibited in-stent restenosis and upregulated SMC contractile protein expression. Overexpression of YAP blocked the antirestenosis effect of SFES and repressed contractile smooth muscle-specific genes in vivo, indicating that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. We demonstrated that SFES attenuated in-stent restenosis through YAP-mediated SMC phenotypic modulation. Targeting SMC phenotypic modulation by drug-eluting stent represents an attractive therapeutic approach for the treatment of occlusive vascular diseases.NEW & NOTEWORTHY In the present study, we demonstrated that sorafenib regulates smooth muscle cell (SMC) phenotypic modulation from a proliferative to a contractile state. Sorafenib induced a myocardin-serum response factor interaction and increased SMC contractile gene transcription through the Yes-associated protein pathway. Moreover, local delivery of sorafenib regulating SMC phenotypic modulation represents a promising strategy in the design of drug-eluting stents.

SCENT Trial.

Background and Purpose- To evaluate the safety and effectiveness of the Surpass Flow Diverter (Surpass; Stryker Neurovascular, Fremont, CA) in the treatment of large or giant wide-neck intracranial aneurysms at one year, we hypothesize that treatment with Surpass meets or improves on historical safety and efficacy end points. Methods- SCENT trial (Surpass Intracranial Aneurysm Embolization System Pivotal Trial to Treat Large or Giant Wide Neck Aneurysms) is a multicenter, prospective, single-arm, nonrandomized, interventional trial of the Surpass Flow Diverter for uncoilable or previously treated but failed aneurysms of the intracranial internal carotid artery extending from the petrous segment to the carotid terminus at its bifurcation into anterior and middle cerebral arteries. For enrollment in SCENT, target aneurysms had to be wide-neck (≥4 mm) and large or giant size (≥10 mm). Study results are compared with performance goals derived from a thorough review of the medical literature. The primary effectiveness end point included 3 components: complete aneurysm occlusion, absence of significant parent artery stenosis (≥50%), and no retreatment at 12 months. The primary safety end point was major ipsilateral stroke (increase in National Institutes of Health Stroke Scale score of ≥4) or neurological death within 12 months. Results- At 26 medical centers, 180 patients with 180 target aneurysms were enrolled in the modified intention-to-treat cohort. Per angiographic core lab assessment, there were 15 (8.3%) fusiform, 164 (91.1%) saccular aneurysms, and 1 (0.6%) blister aneurysm. Mean aneurysm size was 12.0 mm. Thirteen (7.4%) aneurysms were giant (≥25 mm). Fifty-eight (32.2%) aneurysms were located in the supraclinoid and distal (including posterior communicating artery) segments of the internal carotid artery. Mean procedure duration was 53.6 minutes. The device was successfully implanted in 97.8% of patients with a mean of 1.1 devices per patient. SCENT met both primary safety and effectiveness end points: 12-month primary effectiveness rate was 62.8% [(113/180); 95% CI, 55.3-69.9] and 12-month major ipsilateral stroke or neurological death rate was 8.3% [(15/180); 95% CI, 4.7-13.4]. Conclusions- Surpass provides safe and effective flow diversion of large or giant, wide-neck, intracranial internal carotid artery aneurysms. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01716117.

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.

A Young Patient with Emery-Dreifuss Muscular Dystrophy Treated with Endovascular Therapy for Cardioembolic Stroke: A Case Report.

We had a case of Emery-Dreifuss muscular dystrophy (EDMD) in an 18-year-old woman who underwent endovascular therapy for a cardioembolic stroke. At 5 years old, she showed a high creatine kinase level and atrial fibrillation on electrocardiography in our hospital. Finally, she was diagnosed as having EDMD by genetic screening that revealed mutations in the LMNA gene (c.810+1G>T). Before this event, she received no medications. At 18 years old, she was admitted to our hospital>8 hours after the onset of sudden consciousness disturbance. Neurological examination on admission revealed consciousness disturbance and right hemiplegia. Magnetic resonance imaging revealed a cerebral infarction in the left insular cortex and putamen with left internal carotid artery occlusion. We performed endovascular therapy and completely recanalized her left internal carotid artery. Thereafter, her neurological symptoms improved. She was subsequently transferred to a rehabilitation hospital. EDMD is a rare genetic muscular disease that mainly presents with contractures, weakness, and cardiac conduction abnormalities. Although patients with EDMD are young with low CHADS2 score, they have a disease-specific cardiovascular pathogenesis caused by a fatal risk factor. Therefore, we consider anticoagulant therapy necessary to prevent thrombotic events, even if the CHADS2 score is low, in patients with EDMD.

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.

Physical Activity and Characteristics of the Carotid Artery Wall in High-Risk Patients-The SMART (Second Manifestations of Arterial Disease) Study.

BACKGROUND: Physical activity reduces the risk of vascular disease. This benefit is not entirely explained through an effect on vascular risk factors. We examined the relationship of physical activity and characteristics of the carotid artery wall in patients with vascular disease or risk factors. METHODS AND RESULTS: Cross-sectional analyses were performed in 9578 patients from the SMART (Second Manifestations of Arterial Disease) study, a prospective cohort study among patients with vascular disease or risk factors. Physical activity was assessed using questionnaires. Carotid intima-media thickness and carotid artery stenosis of both common carotid arteries was measured. In a subset of 3165 participants carotid diastolic diameter and distension were assessed. Carotid stiffness was expressed as the distensibility coefficient and Young's elastic modulus. Regression analyses adjusted for vascular risk factors showed that physical activity was inversely associated with diastolic diameter (fifth versus first quintile B=-0.13 mm; 95% CI, -0.21 to -0.05) and decreased risk of carotid artery stenosis (relative risk, 0.58; 95% CI, 0.48-0.69). A light level of physical activity was associated with less carotid stiffness (second versus first quintile; Young's elastic modulus B=-0.11 kPa-1×10-3; 95% CI, -0.16 to -0.06; distensibility coefficient B=0.93 kPa×103; 95% CI, 0.34-1.51), but there was no additional benefit with increasing levels of physical activity. In patients with vascular disease, physical activity was inversely associated with common carotid intima-media thickness, but not in patients with vascular risk factors. CONCLUSIONS: In patients with vascular disease or risk factors, increased physical activity was associated with smaller carotid diastolic diameter, decreased risk of carotid artery stenosis, and less carotid stiffness, but it only showed benefits on carotid intima-media thickness in patients with vascular disease.

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury.

BACKGROUND: Despite recent improvements in angioplasty and placement of drug-eluting stents in treatment of atherosclerosis, restenosis and in-stent thrombosis impede treatment efficacy and cause numerous deaths. Research efforts are needed to identify new molecular targets for blocking restenosis. We aim to establish angiogenic factor AGGF1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury. METHODS AND RESULTS: AGGF1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF1+/- mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells (VSMCs) in carotid arteries after vascular injury. Importantly, AGGF1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMCs to the contractile phenotype in mice in vivo. In vitro, AGGF1 significantly inhibits VSMCs proliferation and decreases the cell numbers at the S phase. AGGF1 also blocks platelet-derived growth factor-BB-induced proliferation, migration of VSMCs, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF1 inhibits phenotypic switching of VSMCs to the synthetic phenotype by countering the inhibitory effect of platelet-derived growth factor-BB on SRF expression and the formation of the myocardin/SRF/CArG-box complex involved in activation of VSMCs markers. Finally, we show that AGGF1 inhibits platelet-derived growth factor-BB-induced phosphorylation of MEK1/2, ERK1/2, and Elk phosphorylation involved in the phenotypic switching of VSMCs, and that overexpression of Elk abolishes the effect of AGGF1. CONCLUSIONS: AGGF1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF1-MEK1/2-ERK1/2-Elk-myocardin-SRF/p27 signaling pathway.

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.