bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 180: Risks and Predictors of Ischemic/bleeding Complications in Cardiac Patients Undergoing Elective Non-cardiac Surgery - An Analysis of the Prague-14 Study
Authors: Motovska Zuzana , Dusek Ladislav , Ondrakova Martina , Knot Jiri , Havluj Lukas , Robert Gurlich , Bartoska Radek , Dupa Valer , Bittner Lukas , Widimsky Petr 
Published: March 2022

Objective:
To assess risks and predictors of ischemic/bleeding complications in consecutive patients with at least one cardiovascular disease undergoing elective major non-cardiac surgery.

Methods:
Subgroup analysis of the PRAGUE-14 study was performed. This prospective study analyzed the impact of antithrombotic therapy interruption on outcomes in non-selected surgical patients with known cardiovascular disease. Logistic regression models were applied to assess the association between potential predictors and selected binary coded end-points (perioperative ischemia, bleeding and hospital mortality).

Results:
Study population consisted of 1200 patients, 742 of them underwent elective surgery; age (median) 72.0, 66.2% males, CAD in 396, stroke in 70, atrial fibrillation in 209, venous thromboembolism (VTE) in 55, valvular heart disease in 108, artificial valve in 18, cardiomyopathy in 13.

Preoperatively, 62.0% patients were receiving betablockers, 55.1% ACE inhibitors, 32.9% statins. 84.6% of patients were treated with antithrombotic therapy i.e. 439 aspirin, 31 DAPT, 192 oral anticoagulants. Prophylaxis of VTE in perioperative period was applied in 93.5%.
In-hospital ischemic complications occurred in 3% (vs 9.8% in acutely operated patients, p<0.001), bleeding complications in 10.90% (vs 12.0%, n.s.), and both of them in 0.7% (vs. 4.2%, p<0.001). Mortality of patients, who underwent planned surgery, was 2.2% (vs. 6.8% in acute surgery, p<0.001).
Multivariate linear regression identified that pre-procedural anemia and history of (coronary or non-coronary) stent implantation were significantly related to ischemic complications. Periprocedural antithrombotic management has no impact on ischemic complications. Termination of warfarin less than 4 days before surgery was significantly related to the risk of bleeding.

Conclusions:
Risk of perioperative ischemic complications is significantly lower in cardiac patients who are undergoing non-cardiac surgery electively (in comparison to acutely), and this risk is significantly related to a history of preprocedural anemia and history of stent implantation. For prevention from periprocedural bleeding, warfarin should be discontinued more than 4 days before surgery
Abstract 223: Inhibition of STAT3 Phosphorylation by Sulforaphane Reduces Adhesion Molecule Expression in Vascular Endothelial Cell
Authors: Ahn Hee Y , Cho Young S , Kim Chan H 
Published: March 2022

This study explored the mechanism(s) by which sulforaphane inhibits intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expressions stimulated with lipopolysaccharide (LPS) in human umbilical vein endothelial cell (HUVEC).
The protein levels of ICAM-1 and VCAM-1 were investigated by primary antibodies of anti-human ICAM-1, anti-human VCAM-1. The phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) were investigated by phospho-STAT3 antibody. The STAT3-specific small interfering RNA (siRNA) was used to knockdown the expression of STAT3. THP-1 monocyte adhesion photograph images were obtained using a fluorescence microscope. Sulforaphane prevented LPS-mediated increase of ICAM-1 and VCAM-1 expression. Sulforaphane prevented LPS-mediated increase of STAT3 phosphorylation. AG490, Janus kinase (JAK)-2 inhibitor and Stattic, STAT3 inhibitor, reduced LPS-induced the expressions of ICAM-1 and VCAM-1, respectively. STAT3 small interfering RNA (siRNA) treatment reduced ICAM-1 and VCAM-1 expression stimulated with LPS. Sulforaphane reduced LPS-mediated THP-1 monocyte adhesion to HUVEC. These data provide a novel mechanism where sulforaphane decreases an expression of ICAM-1 and VCAM-1 onto vascular wall through an inhibition of STAT3 phosphorylation.
Abstract 26: Who is Going to Stroke? Biomarkers for the Unstable Carotid Atheroma
Authors: Hedin Ulf , Matic Perisic Ljubica , Iglesias Maria Jesus , Lengquist Mariette , Razuvajev Anton , Roy Joy , Pontén Fredrik , Odeberg Jacob 
Published: March 2022

Unstable carotid stenosis is an important source of extracranial atheroembolism and stroke. Current interventional therapy is based on surrogate markers for stroke risk and no precise diagnostic tool is available for identification of either individuals or lesions at risk. Thus, biomarkers for the unstable carotid atheroma may improve selection of patient for intervention.
Here, a high-throughput pipeline for identification of circulating biomarkers for unstable carotid atherosclerosis was developed. Carotid plaques were part of the Biobank for Karolinska Endarterectomies (BiKE) and obtained from patients treated for symptomatic (S) and asymptomatic (AS) carotid stenosis together with peripheral plasma and ‘local’ plasma (n = 47) sampled after clamping prior to arteriotomy. Screening of proteins was processed through Luminex based, suspension-bead assays using over 10,000 antibodies from the Human Protein Resource (HPR) and compared to peripheral plasma (n = 200 total). Plasma analysis identified 150 significantly dysregulated candidates based on three comparisons: proteins enriched in local plasma compared to peripheral plasma; in local plasma from S compared with AS patients; in peripheral plasma from S compared with AS patients. Pathway analysis revealed that detected proteins were related to ossification, lysosomes, magnesium transport, prenylation, collagens, lipid metabolism, and transcription factors. Identified candidate proteins were further filtered using public database mining, comparisons with transcriptomic data from BiKE, and qPCR/IHC in matched endarterectomies. Among the identified candidates, THEMIS2 and BLVRB were examples of proteins successfully validated as upregulated in both plaques and plasma from S patients and localized to CD68+ macrophages.
Extensive analysis of plasma and tissue samples from patients undergoing carotid surgery permitted identification of several potential biomarkers for unstable carotid atherosclerosis. Further validation in larger cohorts of unstable atherosclerosis is necessary in order to determine predictive power for the identification of individuals at risk as well as for the development of targeted bioimaging for lesion detection.
Abstract 3: Cholesterol Crystals Produced by Endothelial Cells During Hyperlipidemia Initiate Atherogenesis
Authors: Baumer Yvonne , McCurdy Sara , Weatherby-Carvalho Tina , Boisvert William A 
Published: March 2022

Atherosclerosis is caused by prolonged dyslipidemia and chronic inflammation. Although much is known about advanced stages of atherosclerosis, events leading to its initiation are poorly understood. Cholesterol crystals (CC) have been associated with advanced plaque, but their origin and potential role in the initiation of atherosclerosis and early plaque development are unknown. Using polarized light, scanning and transmission electron microscopy we show for the first time that CC are present in the very early plaque induced after only 1 week of high fat diet in ldlr-null mice. We determined that the source of CC is the endothelial monolayer by treatment of human aortic endothelial cells with LDL for 5 days. Other cell types like monocytes, fibroblasts and human umbilical vein endothelial cells failed to form CC upon LDL, AcLDL or oxLDL treatment. To identify in vitro formed CC we used polarized light, transmission electron and confocal microscopy. Furthermore, we identified that CC are generated within autophagolysosomes of the endothelium. The formation of CC by endothelial cells is accompanied with changes in intracellular cAMP levels. The consequences of early subendothelial CC formation are incomplete junction formation with subsequent impaired endothelial barrier integrity, processes known to be involved in atherosclerosis initiation and progression. Interestingly, increase of intracellular cAMP inhibited endothelial CC production in vitro and in vivo. By performing western Blot, flow cytometry and various microscopy techniques we could show that the inhibition of CC-formation as the results of cAMP increase is accompanied by a decrease autophagolysosomes as the CC producing organelles. We could furthermore demonstrate that this protective effect of cAMP could be inhibited by additional application of an eNOS inhibitor.
In summary, we could demonstrate that CC are present in very early stages of atherosclerosis. These early subendothelial CC depositions are produced by autophagolysosomes within the endothelial monolayer in a cAMP/eNOS dependent manner. With these findings we might have found the so far missing link to initiation of plaque development in atherosclerosis.
Abstract 357: Intimal Smooth Muscle Cells Are Vascular Tissue Specific Innate Immune Effector Cell
Authors: Jiang Xintong , Hansson Göran K , Yan Zhongqun 
Published: March 2022

Intimal smooth muscle cells (SMC) represent the largest cell population in atherosclerotic plaques and restenotic lesions. These cells have multiple functions that differ from those of SMC of tunica media. Compared with medial SMC, intimal SMC are hyperresponsive to a large array of endogenous and exogenous inflammatory stimuli. However, the underlying molecular basis is elusive.
Analyzing the phenotype of smooth muscle cells (SMC) isolated from balloon injury induced neointima of rat carotid artery, we found that unlike SMC of tunica media, the SMC of the intima exhibit an innate immune phenotype, characterized by constitutively expressing a broad panel of pathogen pattern recognition receptors (PRR) seen typically in macrophages. These PRR confer on intimal SMC an ability to react to an extensive list of microbial components by producing inflammatory mediators including nitric oxide, cytokines and chemokines. Additionally, intimal SMC produce the leukocyte chemokine CCL-5 (or RANTES) in the absence of exogenous stimuli, implying an intrinsic innate immune activity. The master program that determines the phenotype of intimal SMC remains to be defined but may involve a number of transcription pathways. These observations suggest that intimal SMC are vascular tissue specific innate immune effector cells with functions similar to those of macrophages.
Abstract 403: E-selectin Transfer by Recombinant Adeno-associated Virus Improves Angiogenesis in a Murine Model of Hindlimb Ischemia
Authors: Horkan Davis , Li Yan , Liu Zhao-Jun , Velazquez Omaida 
Published: March 2022

Novel cell-based therapies, including optimization of the wound microenvironment via chemical or genetic means, hold promise to revolutionize the treatment of chronic limb ischemia and ischemic wounds.
We examined the hypothesis that increasing expression in ischemic tissue of the endothelial adhesion molecule E-selectin by adeno-associated viral transduction would promote angiogenesis in a murine model of hindlimb ischemia.
12-week-old female C57BL/6 mice (N=10) underwent unilateral femoral artery ligation. After ligation, each mouse was injected in the ipsilateral semimebranosus muscle with 1x108 viral particles of either adeno-associated virus recombinant with human E-selectin gene (AAV/E-selectin) or adeno-associated virus recombinant with green fluorescent protein gene as control (AAV/GFP) suspended in phosphate-buffered saline (N=5/group).
Ischemia was confirmed by laser Doppler perfusion imaging on post-ligation day one. Mice were sacrificed on post-ligation day seven and semimembranosus muscle harvested from the ligated limb. Muscle was fixed, embedded, and sectioned in 5 μm intervals.
To assess the efficacy of viral transduction, we performed immunohistochemistry (IHC) of each section from the AAV/GFP group with anti-GFP antibody and from the AAV/E-selectin group with anti-human E-selectin antibody.
Angiogenesis was evaluated by capillary density with IHC of all slides for endothelial cell marker VEGFR2 with anti-VEGFR2 antibody.
Relative fluorescence index per high-powered field (RFI) was recorded for each slide. E-selectin RFI was 4 times greater, VEGFR2 RFI was 2 times greater, and E-selectin/VEGFR2 RFI ratio was 2 times greater in AAV/E-selectin treated tissue than in control.
In conclusion, this study demonstrates the AAV/E-selectin vector as an effective means to upregulate E-selectin expression in ischemic muscle and supports E-selectin upregulation as a possible means to improve ischemia-induced angiogenesis.
Abstract 43: Recycling Controls Procoagulant and Cell Signaling Functions of Tissue Factor
Authors: Rothmeier Andrea S , Ruf Wolfram 
Published: March 2022

Macrophages are central orchestrators in the detrimental cycle of inflammation and coagulation in cardiovascular diseases. Cell danger signals in form of high level of extracellular ATP trigger the macrophage P2X7 receptor leading to secretion of pro-inflammatory IL-1β and the release of pro-thrombotic tissue factor (TF) positive microparticles (MP). P2X7 receptor signaling uncouples the thioredoxin-thioredoxin reductase system and induces inflammasome activation leading to decryption of cell-surface TF and its trafficking onto filopodia for incorporation into MP. These MP have a distinct composition of thiol-regulated proteins and a high surface density of procoagulant PS. Besides its well-established function in IL-1β processing and secretion, we found an entirely unexpected role for caspase 1 in the release of TF from the final severing of highly thrombotic TF-positive MP. Thus, caspase 1 directly couples the release of pro-inflammatory and pro-thrombotic mediators.
P2X7 activation not only causes MP release, but also activates cell surface TF that remains non-coagulant without secondary signals on primed macrophages. We observed that cell detachment rapidly induced full TF procoagulant activity, pointing to an important role of cell adhesion in the maintenance of a non-thrombotic state. Stable cell adhesion is controlled by integrin recycling pathways and the small GTPase arf6 is one of the key regulators of these processes. We found that blocking receptor internalization retains TF on the cell surface and markedly enhanced TF procoagulant activity. Under these conditions, TF was associated with integrin β1 and arf6, and importantly, P2X7 receptor activation promoted arf6-GTP hydrolysis to arf6-GDP, indicating interruption of this recycling pathway following stimulation. In addition, increasing arf6-GDP levels, either by pharmacological inhibitor or overexpression of an arf6-mutant, prevented TF-dependent signaling though protease activated receptor 2 (PAR2) and simultaneously increased cellular procoagulant TF activity in epithelial and in melanoma cells. These findings demonstrate an unexpected role for arf6-controlled recycling in the regulation of TF procoagulant and signaling functions.
Abstract 52: Capsaicin Activates the Trpv1-camkii-ampk-sirt-1-dependent Mechanism to Trigger Brown Remodeling of White Adipocytes to Antagonize Diet-induced Obesity
Authors: Thyagarajan Baskaran , Ren Jun , Baskaran Padmamalini 
Published: March 2022

Obesity is a leading cause of metabolic syndrome. The growing endemic of diet-induced obesity necessitates the development of novel strategies to counter obesity. Recent research suggests a regulatory role of transient receptor potential vanilloid 1 (TRPV1) in diet-induced obesity. Here, we evaluated the hypothesis that capsaicin (CAP), a TRPV1 agonist, inhibited high fat diet (HFD)-induced obesity by inducing browning of white adipose tissue (WAT).
Dietary CAP (0.01% of HFD) significantly prevented obesity in wild type (WT) but not in TRPV1-/- mice without modifying the food/water intake in these mice. CAP increased the expression of the brown fat-specific thermogenes, peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1 alpha, uncoupling protein-1 and bone morphogenetic protein b8 in the subcutaneous and brown fat pads of WT mice in vivo. Furthermore, CAP increased the expression of sirtuin-1 (SiRT-1 deacetylase) and PR domain protein 16 (PRDM-16-gene responsible for the molecular switch of white to brown fat) in WAT. CAP-triggered deacetylation of PPARγ and PRDM-16 by activating SiRT-1 to facilitate the PPARγ-PRDM-16 interaction and initiate browning of WAT. This effect also corresponded with increased respiratory coefficient, heat production and locomotor activity in CAP-fed WT mice.
Analysis of mechanism of action of CAP revealed that CAP activated TRPV1-dependent signaling cascade of Ca2+/calmodulin-dependent protein kinase II (CaMKII)- 5’ adenosine monophosphate-activated protein kinase (AMPK) and increased the phoshorylation of CaMKII, AMPK and SiRT-1 as well as SiRT-1 activation. Pharmacological inhibition of CaMKII by KN-62 (5 μM; 1 hr. preincubation), inhibition of TRPV1 by capsazepine (10 μM; 1 hr. preincubation) or chelation of intracellular Ca2+ by BAPTA-AM (10 μM; 1 hr preinbubation) prevented the effects of CAP (1μM; 30 min. treatment) on SiRT-1 phosphorylation.
Collectively, our data unambiguously suggest that CAP prevents HFD- induced obesity by stimulating browning of WAT through TRPV1 activation and uncover a novel role of TRPV1-stimulated intracellular Ca2+-dependent CaMKII-AMPK-SiRT-1 signaling cascade in the browning of WAT.
Abstract 554: Vascular Lesion Formation is Attenuated by Genetic Deletion of Hyaluronan Synthase 3
Authors: Dick Lena S , Homann Susanne , Mueller Julia , Grandoch Maria , Fischer Jens W 
Published: March 2022

An extensive accumulation of the matrix component hyaluronan (HA) has been observed in vascular lesions. HA is thought to confer immunomodulatory actions and to regulate cell proliferation and migration in diseased vessels. HA is extruded into the extracellular space by three transmembrane HA-synthase isoenzymes (HAS1, -2, -3).
Objective of the current study was to assess specifically the role of HAS3 in vascular pathologies such as restenosis and atherosclerosis.
In HAS3 deficient mice (HAS3-/-) and wildtype controls (WT) neointimal hyperplasia was induced using a carotid artery ligation model. Morphometric analysis of carotid arteries harvested 28 days after ligation revealed that lack of HAS3 mitigates neointimal lesion formation as indicated by a decrease in intimal area (AUC: HAS3-/-, 1.53 x107 ± 0.23 x107 μm3 vs. WT, 2.59 x 107 ± 0.34 107 μm3, n = 9, p < 0.05) and reduced intima/media ratio (HAS3-/-, 0.94 ± 0.13 vs. WT, 1.39 ± 0.13, n = 9, p < 0.05). Supportive in vitro studies suggest that blunted neointimal hyperplasia is mainly due to a reduced migration and to a lesser extent reduced proliferation of vascular smooth muscle cell (VSMC).
Next atherosclerosis-prone apolipoprotein E/HAS3 double-deficient (apoE-/-/HAS3-/-) mice were generated and fed with a cholesterol-rich Western type diet for 15 weeks. Analysis of aortic en face preparations stained with Oil Red O revealed reduced plaque burden compared to apoE-/- controls (apoE-/-/HAS3-/-, 6.95 ± 2.66, n = 10 vs. apoE-/-, 11.43 ± 4.06, n = 13, p < 0.05). Plasma lipids (total cholesterol, LDL/VLDL, HDL cholesterol) did not differ between the groups. Plaque composition at the aortic root showed decreased collagen content (Picro Sirius Red staining) but no differences in cell density, VSMC content (alpha Actin staining) and macrophage count (Mac2 staining). In contrast, flow cytometry data point to a reduction in circulating T cells (apoE-/-/HAS3-/-, 28.4 ± 1.2 %, n = 5 vs. control, 41.7 ± 5.1 %, n = 6).
Collectively, these findings suggest a role for HAS3 in vascular lesion formation. In neointimal hyperplasia HAS3-dependent HA synthesis may support mainly VSMC migration whereas in atherogenesis additional immunomodulatory actions are proposed.
Abstract 564: CD146 Deficiency Leads to Accelerated Atherosclerosis in Mice
Authors: Blin Muriel G , Bachelier Richard , Fernandez Samantha , Guillet Benjamin , Fallague Karim , Robert Stéphane , Bardin Nathalie , Blot-Chabaud Marcel , Dignat-George Françoise , Leroyer Aurelie S 
Published: March 2022

Atherosclerosis is a chronic inflammatory disease of the large vessels and its progression is based in part on the continued recruitment of macrophages in the inflammatory wall. The well described role of CD146 in leukocyte infiltration in vitro suggests a role for this endothelial junction molecule in the early stages of the formation of atherosclerotic plaques. However, the involvement of CD146 in atherogenesis has not been elucidated.
To investigate the role of CD146 deficiency in atherosclerosis, CD146 knocked-out (KO) mice were bred with ApoE KO mice. Mice were fed a high-fat Western diet for 24 weeks and were monitored for aortic wall thickness using high frequency ultrasound. After 24 weeks of diet, the arterial wall thickness was significantly higher in CD146 deficient mice (0.19±0.01mm vs 0.27±0.01mm; p=0.012) and there was a significant 47 % increase (p=0.015) in total aortic lesion area, evaluated by histological oil red O coloration. However, mice weights and total cholesterol plasma levels were similar between the two groups of mice. We detected a 2-fold increase in macrophage recruitment to the atherosclerotic plaque of the double KO mice compared with ApoE KO mice, suggesting that the atherosclerotic lesions in these mice were more inflammatory. In addition, CD146 deficient plaques contained significantly less smooth muscle cells (p=0.036) and could be more vulnerable. We observed a maladaptive immune response in double KO mice since the circulating neutrophils and monocytes were significantly increased (p=0.008 and p=0.015 respectively) in the absence of CD146 whereas circulating T lymphocytes were significantly decreased (p=0.026). In a similar way, splenocytes isolated from double KO mice contained significantly lower levels of T cells (p=0.002), suggesting a default of adaptive immunity in the absence of CD146 during atherosclerosis.
Our results demonstrated the involvement of CD146 in the progression of atherosclerosis in mice. Our data also suggest that CD146 is involved in the regulation of adaptive immune response and its absence lead to an inflammatory phenotype, which could influence atherosclerosis plaque fate. Thus, CD146 should be considered as a potential target for protection against atherosclerosis.