Abstract 618: Targeted Delivery of microRNA-146a/-181b Protects Against Endothelial Dysfunction and Prevents Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Wing Tak Wong ◽  
Shuangtao Ma ◽  
Yu Huang ◽  
Xiaoyu Tian
Keyword(s):  
Endothelial Dysfunction ◽  
Targeted Delivery ◽  
Carotid Arteries ◽  
Vascular Inflammation ◽  
Developed Countries ◽  
Treated Group ◽  
Western Diet ◽  
Systemic Delivery ◽  
Vascular Regulation ◽  
Angioplasty And Stenting

Objective: Atherosclerosis, which underlies most cardiovascular diseases (CVD), is a leading cause of mortality and disability in developed countries. The endothelium is an important site of vascular regulation, and its dysfunction initiates atherosclerosis and supports its progression. Current drug therapies, percutaneous angioplasty, and stenting alleviate symptoms but do not reverse atherosclerosis. Thus, more effective strategies that prevent or reverse atherosclerosis via improved endothelial function are needed. Approach: E-selectin serves as a surface marker of inflamed endothelial cells (ECs). We attempted to deliver microRNA (miR)-146a and miR-181b to inflamed endothelium covering atherosclerotic plaques with an E-selectin-targeting multistage vector (ESTA-MSV to inhibit atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and then loaded into ESTA-MSV microparticles. Male apolipoprotein E-deficient mice were fed with Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Results: Atherosclerotic plaque size decreased with treatment of miRs packaged in ESTA-MSV but not in PEG/PEI. Moreover, vascular inflammation markers such as macrophages in aortic root lesion and expression of chemokines in aortic tissues were decreased while the vascular smooth muscle cells and collagen were increased in plaques from ESTA-MSV/miRs-treated mice compared with vehicle-treated group. Systemic delivery of miR-146a/-181b significantly improved the ACh-induced relaxation of aortas and carotid arteries and inhibited ACh-induced endothelium-dependent contraction of carotid arteries of ApoE-/- mice fed with Western diet for 12 weeks Conclusions: Our data demonstrate that the ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates the endothelial dysfunction and prevents atherosclerosis.

scholarly journals The Evolution of Safe and Effective Coaguligands for Vascular Targeting and Precision Thrombosis of Solid Tumors and Vascular Malformations

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 776
Author(s):  
Fahimeh Faqihi ◽  
Marcus A. Stoodley ◽  
Lucinda S. McRobb
Keyword(s):  
Ischemic Stroke ◽  
Targeted Delivery ◽  
Vascular Malformations ◽  
Thrombus Formation ◽  
Developed Countries ◽  
Coagulation Cascade ◽  
Vascular Targeting ◽  
Systemic Delivery ◽  
Vessel Occlusion ◽  
Vessel Patency

In cardiovascular and cerebrovascular biology, control of thrombosis and the coagulation cascade in ischemic stroke, myocardial infarction, and other coagulopathies is the focus of significant research around the world. Ischemic stroke remains one of the largest causes of death and disability in developed countries. Preventing thrombosis and protecting vessel patency is the primary goal. However, utilization of the body’s natural coagulation cascades as an approach for targeted destruction of abnormal, disease-associated vessels and tissues has been increasing over the last 30 years. This vascular targeting approach, often termed “vascular infarction”, describes the deliberate, targeted delivery of a thrombogenic effector to diseased blood vessels with the aim to induce localized activation of the coagulation cascade and stable thrombus formation, leading to vessel occlusion and ablation. As systemic delivery of pro-thrombotic agents may cause consternation amongst traditional stroke researchers, proponents of the approach must suitably establish both efficacy and safety to take this field forward. In this review, we describe the evolution of this field and, with a focus on thrombogenic effectors, summarize the current literature with respect to emerging trends in “coaguligand” development, in targeted tumor vessel destruction, and in expansion of the approach to the treatment of brain vascular malformations.

Abstract 12375: Vascular Inflammation Evaluated by 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography is Associated With Endothelial Dysfunction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Akihiro Honda ◽  
Nobuhiro Tahara ◽  
Atsuko Tahara ◽  
Sachiyo Igata ◽  
Yoshikazu Nitta ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Positron Emission Tomography ◽  
Endothelial Dysfunction ◽  
Pet Imaging ◽  
Carotid Arteries ◽  
Vascular Inflammation ◽  
Emission Tomography ◽  
Percent Change ◽  
Positron Emission ◽  
Fat Volume

Background: Endothelial dysfunction is an initial step for atherosclerotic cardiovascular disease. However, involvement of vascular inflammation in endothelial dysfunction is not fully investigated in humans. We assessed the relationship between endothelial function and vascular inflammation evaluated by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging. Methods and Results: We examined endothelial function and vascular inflammation, which were evaluated by flow-mediated dilation (FMD) of the brachial artery functionally and FDG-PET imaging of carotid arteries, respectively, in 128 subjects (83 males and 45 females; mean age 61.8 ± 10.0 years) who underwent a risk-screening test for cardiovascular disease in Kurume University Hospital. Vascular inflammation of the carotid arteries was measured by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR). Mean percent change in vasodilation (percent change over the baseline values; %FMD) and carotid TBR were 5.60 ± 2.24 % and 1.43 ± 0.22, respectively. %FMD was less in men than in women. In univariate analysis, %FMD was inversely correlated with age (p=0.011), systolic blood pressure (p=0.014), carotid artery maximum intima-media thickness (p=0.014), HbA1c (p=0.020), visceral fat volume (p=0.005), or TBR values (p<0.001). Multiple stepwise regression analysis revealed that age (p=0.034), visceral fat volume (p=0.002), and TBR values (p<0.001) were independently associated with decreased %FMD (R2=0.245). Conclusions: We found here that vascular inflammation in the carotid arteries evaluated by FDG-PET was one of the independent association of decreased %FMD, thus suggesting that vascular inflammation might contribute to endothelial dysfunction in humans.

Abstract 276: Systemic Delivery of Microrna-146a Improves Endothelial Function and Ameliorates Atherosclerosis in Apolipoprotein E-deficient Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Shuangtao Ma ◽  
Xiao Yu Tian ◽  
Chaofeng Mu ◽  
Haifa Shen ◽  
Yunrong Zhang ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Apolipoprotein E ◽  
Carotid Arteries ◽  
Treated Group ◽  
Vehicle Group ◽  
Early Event ◽  
Aortic Tissue ◽  
Systemic Delivery ◽  
Plaque Area ◽  
Deficient Mice

Rationale: Endothelial inflammation is an early event in the development of atherosclerosis. The microRNA (miR)-146a showed anti-inflammatory effects in cultured endothelial cells. In this study, we investigated the therapeutic role of miR-146a in endothelial function and atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods and Results: The miR-146a was packaged into a multistage vector (MSV) that was conjugated with an E-selectin-targeting thioaptamer (ESTA) to form an ESTA-MSV microparticle. The ApoE-deficient mice were fed with Western diet and injected through tail vein with 15μg of miR-146a loaded ESTA-MSV microparticles or vehicle vectors biweekly for 12 weeks. The expressions of miR-146a in aortic tissue was increased by five times at two weeks after injection. However, the expressions of miR-146a in heart, lung, liver, spleen, kidney, and skeletal muscle were not increased. The acetylcholine-induced endothelium-dependent relaxations in both carotid arteries and aortas were significantly improved in mice from miR-146a treated group compared with vehicle group. In addition, the endothelium-dependent contractions of carotid arteries were also improved by miR-146a treatment. The en face oil red O staining of whole aortas showed the plaque area was decreased in miR-146a-treated mice. Application of miR-146a also decreased the plaque size, macrophages, and T-lymphocytes, but increased the collagen deposition and vascular smooth muscle cells in the sections of aortic roots. The PCR results showed that expressions of chemokine (C-C motif) ligand (CCL)-2, CCL-5, and CCL-8 were decreased by miR-146a. Conclusions: E-selectin-targeting delivery of miR-146a improves endothelial function and inhibits atherosclerosis.

scholarly journals Effect of spironolactone for 1 yr on endothelial function and vascular inflammation biomarkers in renal transplant recipients

2019 ◽  
Vol 317 (3) ◽  
pp. F529-F539 ◽  
Author(s):  
Line A. Mortensen ◽  
Claus Bistrup ◽  
Jane Stubbe ◽  
Mattias Carlström ◽  
Antonio Checa ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Renal Transplant ◽  
Endothelial Function ◽  
Adhesion Molecule ◽  
Mineralocorticoid Receptor ◽  
Vascular Inflammation ◽  
Treated Group ◽  
Transplant Patients ◽  
Mineralocorticoid Receptor Antagonism ◽  
Renal Transplant Patients

Kidney transplantation is associated with increased cardiovascular risk. Endothelial dysfunction and vascular inflammation contribute to negative outcome. In experimental models, mineralocorticoid receptor antagonists improved endothelial function and reduced inflammation. The present study tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone improves endothelial function and reduces vascular inflammation in renal transplant patients. Eighty prevalent renal transplant patients from an ongoing, double-blind randomized placebo-controlled trial were included. Paired plasma samples before and after 1 yr of treatment ( n = 39 in the spironolactone-treated group and 41 in the placebo-treated group) were used to determine markers of endothelial dysfunction (nitrite, nitrate, cGMP, arginine, citrulline, ornithine, asymmetric dimethylarginine, symmetric dimethylarginine, NG-monomethyl-l-arginine, von Willebrand factor, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor 1 antigen) and markers of inflammation (intercellular adhesion molecule, vascular adhesion molecule, high-sensitivity C-reactive protein, and serum amyloid protein A). The median time since the transplantation was 4.6 (0.12–22.3) yr in the spironolactone-treated group and 2.1 (0.17–13.9) yr in the placebo-treated group ( P > 0.05). Spironolactone increased plasma aldosterone ( P < 0.001) and K+ ( P < 0.001). Blood pressure did not change significantly. No significant differences were detected between groups in any of the measured markers of endothelial dysfunction or inflammation except in the subgroup analysis of patients with diabetes, where spironolactone decreased nitrite compared with placebo. In this study, mineralocorticoid receptor antagonism did not improve biomarkers of endothelial dysfunction or vascular inflammation in prevalent renal transplant patients. Further studies are needed to evaluate the potential beneficial effect of early or late mineralocorticoid receptor antagonism on vascular outcomes in renal transplant patients.

scholarly journals Evaluation of Endothelial Dysfunction and Autophagy in Fibromyalgia-Related Vascular and Cerebral Cortical Changes and the Ameliorative Effect of Fisetin

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 48
Author(s):  
Fatma Mohamed Ghoneim ◽  
Salwa Mohamed Abo-Elkhair ◽  
Ayman Zaky Elsamanoudy ◽  
Dalia A. Shabaan
Keyword(s):  
Endothelial Dysfunction ◽  
Carotid Arteries ◽  
Caspase 3 ◽  
Rna Extraction ◽  
Pain Syndrome ◽  
Treated Group ◽  
Albino Rats ◽  
Tissue Samples ◽  
Tnf Α ◽  
Ameliorative Effect

Fibromyalgia (FM) is a common chronic pain syndrome that affects 1% to 5% of the population. We aimed to investigate the role of endothelial dysfunction and autophagy in fibromyalgia-related vascular and cerebral cortical changes in a reserpine-induced rat model of fibromyalgia at the histological and molecular levels and to study the ameliorative effect of fisetin. Forty adult female albino rats were divided into four groups (10 each): two control groups, the reserpine-induced fibromyalgia group, and the fisetin-treated group. The carotid arteries and brains of the animals were dissected. Frozen tissue samples were used for total RNA extraction and qPCR analysis of eNOS, caspase-3, Bcl-2, LC-3, BECN-1, CHOP, and TNF-α expression. Histological, immunohistochemical (eNOS), and ultrastructure studies were conducted. The carotid arteries revealed excessive autophagy and endothelial, vascular, and apoptotic changes. The cerebral cortex showed similar findings apart from endoplasmic reticulum stress. Additionally, there was decreased gene expression of eNOS and Bcl-2 and increased expression of caspase-3, LC-3, BECN-1, CHOP, and TNF-α. In the fisetin-treated rats, improvements in the histological and molecular results were detected. In conclusion, oxidative stress, enhanced apoptosis, and excessive autophagy are fundamental pathophysiologic mechanisms of reserpine-induced fibromyalgia. Moreover, fisetin has an ameliorative effect against fibromyalgia.

Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases

2020 ◽  
Vol 26 (30) ◽  
pp. 3633-3651 ◽  
Author(s):  
Javier Blanco-Rivero ◽  
Fabiano E. Xavier
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Phosphodiesterase Inhibitors ◽  
Developed Countries ◽  
Major Health Problem ◽  
Pde Inhibitors ◽  
Pharmaceutical Industries

Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3&#039;, 5&#039;-monophosphate (cGMP) and adenosine 3&#039;, 5&#039;-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

P717Glucagon-like peptide 1 (GLP-1) improves endothelial dysfunction and vascular inflammation in polymicrobial sepsis induced by cecal ligation and puncture (CLP)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Steven ◽  
J Helmstaedter ◽  
F Pawelke ◽  
K Filippou ◽  
K Frenies ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Endothelial Dysfunction ◽  
Knockout Mice ◽  
Vascular Inflammation ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Glucose Levels ◽  
Dpp4 Inhibitor ◽  
Cardioprotective Effects

Abstract Objective Sepsis causes severe hypotension, accompanied by high mortality in the setting of septic shock. LEADER, SUSTAIN-6 and other clinical trials revealed cardioprotective and anti-inflammatory properties of GLP-1 analogs like Liraglutide (Lira). We already demonstrated improved survival by amelioration of disseminated intravasal coagulation (DIC) in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of the GLP-1 degrading enzyme dipeptidylpeptidase-4 (DPP-4). With the present study we aim to investigate the mechanism of protective effects of the GLP-1 analog Lira and the DPP4 inhibitor Linagliptin (Lina) in the clinically relevant sepsis model cecal ligation and puncture (CLP). Methods C57/BL6j and endothelial cell-specific GLP-1 receptor knockout mice (Cdh5crexGLP-1rfl/flmice) were used and sepsis was induced by cecal ligation and puncture (CLP). DPP4 inhibitor (Lina, 5mg/kg/d; 3 days) and GLP-1 analog (Lira, 200μg/kg/d; 3 days) were applied subcutaneously. Aortic vascular function was tested by isometric tension recording. Aorta and heart tissue was used for Western blotting, dot blot and qRT-PCR. Endogenous GLP-1 (7–36 and 9–36) and insulin was determined by ELISA. Blood samples were collected for examination of cell count, oxidative stress and glucose levels. Results Body temperature was increased by CLP and normalized by Lina and Lira. Sham- and Lira- but not Lina-treated septic mice showed low blood glucose levels compared to healthy controls. Acetylcholine-induced (endothelium-dependent) vascular relaxation in aorta was impaired by CLP. This was accompanied by vascular inflammation and elevation of IL-6, iNOS, ICAM-1, and TNF-alpha mRNA levels in aortic tissue. Vascular, cardiac and whole blood oxidative stress were increased by CLP. Furthermore, we detected higher levels of IL-6, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-NHE) in plasma of CLP animals. Lina and Lira reduced oxidative stress and vascular inflammation, which was accompanied by improved endothelial function. In addition, CLP treatment in endothelial specific knockout mice of the GLP-1r strongly induced mortality compared to WT mice, with the effect being strongest in the Lira-treated group. Conclusion The present study demonstrates that Lina (DPP4 inhibitor) and the GLP-1 analog Lira ameliorate sepsis-induced endothelial dysfunction by reduction of vascular inflammation and oxidative stress. Clinical trials like LEADER and SUSTAIN-6 proved that GLP-1 analogs like Lira have cardioprotective effects in T2DM patients. The present study, performed in a clinically relevant model of polymicrobial sepsis, reveals that the known cardioprotective effects of GLP-1 might be translated to other diseases which affect the cardiovascular system like sepsis, underlining the potent anti-inflammatory effects of GLP-1 analogs.

Angioplasty and Stenting of the Extracranial Carotid Arteries

1998 ◽  
Vol 5 (4) ◽  
pp. 293-304 ◽  
Author(s):  
Michel Henry ◽  
Max Amor ◽  
Isabelle Masson ◽  
Isabelle Henry ◽  
Kiril Tzvetanov ◽  
...  
Keyword(s):  
Carotid Arteries ◽  
Angioplasty And Stenting

Validity of ultrasound arterial wall vascularization for assessment of vascular inflammation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
W Sato ◽  
Y Kobayashi ◽  
M Otaka ◽  
M Unuma ◽  
T Yamanaka ◽  
...  
Keyword(s):  
Carotid Stenosis ◽  
Predictive Value ◽  
Arterial Wall ◽  
Carotid Arteries ◽  
Vascular Inflammation ◽  
False Negative ◽  
Intraplaque Hemorrhage ◽  
Funding Source ◽  
Negative Finding ◽  
18F Fdg

Abstract Background Vascular inflammation plays a fundamental role in most vascular diseases including atherosclerosis and vasculitis syndrome, in which arterial wall vascularization (AWV) frequently develops. Visualization of AWV is informative in detecting the vascular inflammation but is challenging. A new ultrasound technique (superb micro-vascular imaging [SMI]) allows the detection of extremely low-velocity flows. We examined an availability of SMI for assessment of the instability of atherosclerotic plaques and the activity of Takayasu arteritis (TA). Methods and results The study consists of two independent and consecutive parts A and B, examined in carotid stenosis (A) and TA (B), respectively. In part A, 12 patients with symptomatic severe carotid stenosis (CS group) scheduled for carotid endarterectomy were enrolled. In six of 12 patients, preoperative ultrasonography with SMI showed intraplaque neovascularization at the plaque shoulder. Postoperatively, histopathology confirmed the neovessels at the corresponding sites of visualized AWV. SMI had a sensitivity of 67%, specificity of 90% for detection of AWV in CS group. In SMI analysis, false positive findings were caused by motion artifact and arterial wall calcification, and a false negative finding is attributed by intraplaque hemorrhage. In part B, 10 patients with TA were enrolled. All patients underwent 18F-FDG-PET/CT, and its vascular uptake were compared with AWV detected by SMI. Bilateral common carotid arteries (CCA), internal carotid arteries and common iliac arteries were examined by SMI. Active vascular 18F-FDG uptake (max SUV &gt;2.1) were found at five sites in three patients, which were not significantly correlated with the prevalence of macaroni sign, increase in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Of note, SMI revealed AWV at five sites corresponding to uptake of 18F-FDG, with a sensitivity/specificity of 100% and 98%, positive predictive value 71%, and a negative predictive value 100%. Conclusion SMI enables visualization of AWV at vulnerable plaque in CS patients and at 18F-FDG positive sites in TA patients. SMI has potential as a modality to detect the vascular inflammation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research, Japan

Sign in / Sign up

Export Citation Format

Share Document