bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 135: Exploration and Modulation of TREM-1 in Experimental Atherosclerosis
Authors: Potteaux Stephane , Joffre Jeremie , Esposito Bruno , Tedgui Alain , Gibot Sebastien , Mallat Ziad , Ait Oufella Hafid 
Published: July 2021

Under conditions of atherosclerosis, monocytes are rapidely recruited into the vessel wall where they differentiate into macrophages. Both classical and nonclassical monocytes are continuously recruited to the lesion and contribute to atherosclerosis formation. Whereas the number of circulating monocytes correlates with plaque development, decrease in their number or migration is protective.
Upon differentiation, macrophages increase TLR expression, which triggers the inflammatory response.
The triggering receptor expressed on myeloid cells (TREM-1) has been shown to amplify TLR-induced signals in sepsis or inflammatory bowel disease. TREM-1 is also produced in a soluble form and is a predictive factor during sever infections in humans. We addressed for the first time the role of TREM-1 in atherosclerosis.
We found preferential expression of TREM-1 on blood neutrophils and nonclassical monocytes in both ApoE+/+ and ApoE-/- mice, but sTREM-1 was only detectable in plasma of ApoE-/- mice (ELISA). TREM-1 expression was significantly increased on both cell types in APOE-/- mice after 4 weeks of high fat diet (Flow cytometry). We next addressed the role of TREM-1 in atherosclerosis formation by injection of a TREM-like transcript 1-derived peptide (LR12) in 8 week-old ApoE-/- mice (daily injection for 4 weeks of LR12 or peptide scramble as control).
We found that pharmaceutical inhibition of TREM-1 significantly reduced plaque formation by 30% without change in cholesterol levels. This was associated with significant reduction in macrophage accumulation after treatment with LR12 (57735,34 μm2 vs 78398,38 μm2 in controls; p=0,004). We demonstrated that LR12 treatment induced a specific rapid and sustained decrease in circulating nonclassical monocytes after 7 days of treatment. By using an in vivo pulse labeling method to quantify monocyte migration, we found that LR12 also altered nonclassical monocyte recruitment to the plaque.
Taken together, these data indicate that TREM-1 expression increases in the context of atherosclerosis and that pharmacological inhibition of TREM-1 protects against plaque development through decreased number and infiltration of nonclassical monocytes.
Abstract 141: The Loss of Nrf2 Enhances Vascular Inflammation but Reduces Atherosclerosis via Effects on Plasma Lipids in LDL Receptor Deficient Mice Fed High Fat Diet
Authors: Ruotsalainen Anna-Kaisa , Tapper Emmi , Lappalainen Jari , Ylä-Herttuala Seppo , Levonen Anna-Liisa 
Published: July 2021

OBJECTIVE
Transcription factor NF-E2-related factor 2 (Nrf2) regulates antioxidant and detoxifying enzymes affording cytoprotection in the cardiovascular system. We have previously reported that Nrf2 deficiency specific to bone marrow derived cells aggravates atherosclerosis in LDL receptor deficient (LDLR-/-) mice. Furthermore, Nrf2 deficiency in macrophages enhances foam cell formation and promotes the proinflammatory phenotype. In contrast, the total loss of Nrf2 has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in apoE-model is currently unknown, but combined systemic and local vascular effects have been proposed. Given these contrasting results, we aimed at assessing the effect of total loss of Nrf2 on atherogenesis in hypercholesterolemic LDLR-/- mice.

METHODS AND RESULTS
Nrf2-/- mice were cross-bred to LDLR-/- mice and fed a high fat diet (HFD) for 6 or 12 weeks. The degree of atherosclerosis was assessed from the cross-sections of proximal aorta. Nrf2 deficiency decreased atherosclerosis in females from 17.2±8.7 % (mean ±SD, n=11-25) to 12.3±4.6 % (p=0.1) and in males from 11.2±3.9 % to 7.6±4.6 % (p=0.025) after 6 weeks on HFD. After 12 weeks on HFD the effects were more pronounced, as Nrf2 deficiency decreased atherosclerosis from 36.5±5.5 % to 30.3±3.5 % in females (p=0.001) and from 30.6±5.7 % to 21.3±6.9 % in males (p=0.005). Nrf2 deficiency also increased the macrophage content relative to lesion area. Supporting systemic effects, Nrf2 deficiency reduced plasma total cholesterol from 24.0±8.4 mmol/l to 10.6±6,7 mmol/l (p=0.006) and triglyceride levels from 3.6±1.4 mmol/l to 1.7±1.2 mmol/l (p=0.008) in males after 6 weeks on HFD.

CONCLUSIONS
In contrast to bone marrow specific Nrf2 deficiency, total loss of Nrf2 aggravates atherosclerosis in LDLR-/- mice likely via systemic effects on lipid metabolism.
Abstract 168: Impact of Obesity and Atrial Fibrillation on Arterial Stiffness
Authors: Willoughby Scott R , Dickinson Kacie , Schultz Carlee , Sanders Prashanthan , Clifton Peter , Keogh Jennifer 
Published: July 2021

Introduction
Turbulent blood flow which occurs in atrial fibrillation patients due to an irregular heart rate may lead to vascular abnormalities and increased thrombotic risk. Obesity is an important emerging substrate for the development of atrial fibrillation. Obesity is also associated with endothelial dysfunction and increased arterial stiffness. We sought to determine the impact of obesity on arterial stiffness in patients with atrial fibrillation.

Methods
34 patients with atrial fibrillation (age 59±12 years,) were evaluated in lean (n=21) and obese (n=13) subgroups, and compared to age-matched lean (n=15) and obese (n=14) control subjects. Arterial stiffness was assessed using radial applanation tonometry (SphygmoCor). Heart rate adjusted aortic augmentation index (AIx: a measure of arterial stiffness) was calculated from the corresponding waveforms utilizing validated transfer functions.

Results
Obese controls and obese atrial fibrillation patients had significantly higher AIx (arterial stiffness) than lean controls and lean atrial fibrillation patients (p=0.003 and p=0.03, respectively: Figure). There was no difference in AIx scores between obese atrial fibrillation patients and obese control subjects (p=0.3) and between lean atrial fibrillation and lean control subjects (p=0.8).

Conclusion
We conclude that obesity is associated with arterial stiffness and atrial fibrillation does not add additional burden. These results suggest the interaction between obesity and atrial fibrillation may contribute to the observed increase in thromboembolic risk, in part, through vascular abnormalities other than increased arterial stiffness.
Abstract 169: Type 2 Diabetes-Induced Hematopoietic Stem Cell Oxidant Stress Attenuates the Differentiation, Skews M1/M2 Specification of Monocytes/Macrophages and Delays Wound Healing in db/db Mice
Authors: Yan Jinglian , Tie Guodong , Wang Shouying , Messina Louis 
Published: July 2021

Rationale
After recruitment to wounds, monocytes differentiate into macrophages which play a central role in all stages of wound healing. Wound healing is significantly delayed in type 2 diabetes and it is related to macrophage specification into M1/M2 phenotype, but the mechanism remains unknown.

Objective
This study tested the hypothesis that type 2 diabetes induces hematopoietic stem cells (HSCs) oxidant stress that reduces their differentiation towards monocytes and skews the specification of M1/M2 phenotype, thereby causing delayed wound healing.

Methods and Results

HSCs were sorted from bone marrow of WT and db/db type 2 diabetic mice. DCF staining showed significant oxidant accumulation in HSCs from db/db mice which was reversed by the antioxidant, N-acetylcysteine (NAC). Bone marrow monocyte concentration (FACS analysis of cell surface markers f4/80, cd14 and cd115) was significantly lower in db/db mice than in WT mice. NAC also reversed the reduced differentiation towards monocyte. Wound closure rate was significantly delayed in db/db mice. Macrophages were isolated from wounds and their concentration and M1/M2 phenotype were quantified by flow cytometry. During the
inflammatory phase
of wound healing, macrophage concentration was decreased and the proportion of M1 macrophage was lower in db/db mice than in WT mice. During
new tissue formation phase
, macrophage concentration was decreased and the proportion of M2 macrophage was lower, but M1 macrophage was higher in db/db mice than in WT mice. During
tissue remodeling phase
, macrophage concentration was increased and M1 macrophage remained higher in db/db mice, but no difference was observed in the proportion of M2 macrophage. The reduced differentiation of HSCs towards monocytes and the delayed wound closure phenotype of db/db mice could be transferred to WT mice by transplanting db/db HSCs into lethally irradiated WT mice.

Conclusion
Type 2 diabetes-induced HSC oxidant stress impairs HSC differentiation towards monocytes, skews the M1/M2 specification of macrophages and thereby accounts for the delayed wound healing. Type 2 diabetes-induced HSC oxidant stress may be a heretofore unrecognized critical regulator of dysinflammation in type 2 diabetes.
Abstract 172: The Effects of Renal Function on Platelet Reactivity in Patients Treated with Clopidogrel and Admitted for Major Adverse Cardiovascular Events in a Community Setting
Authors: Davila Carlos , Vargas Fernando , Monaco Thomas , Huang Kuan-Hsiang Gary , Morris D L , Figueredo Vincent M , Christian Witzke 
Published: July 2021

Introduction
Increased platelet reactivity (PR) while on antiplatelet therapy is associated with worse outcomes. There are conflicting results regarding the influence of renal function on PR in patients taking clopidogrel. Here we assessed the relationship between renal function, PR, and outcomes in a community practice setting.

Methods
We retrospectively reviewed 98 consecutive, non-dialysis patients admitted for major adverse cardiovascular events (MACE) to our institution between 2011 and 2012 that had PR values measured with the VerifyNow P2Y12 Assay. High PR was defined as a PRU >230 and low PR as a PRU ≤178. Renal function was classified based on estimated glomerular filtration rate at the time of assay. All cause mortality, readmissions, length of stay (LOS), and number of cardiac catheterizations were reviewed over 455 days.

Results
The prevalence of PRU>230 was 100% in stage 4 and 5 CKD, 42.9% in stage 3, 53.8% in stage 2, and 53.3% in stage 1 (p=0.049, figure 1). In patients presenting with acute coronary syndromes (n=49), a significant positive association existed between PRU and total number of cardiac catheterizations (p=0.014). Overall patients with PRU value >230 had longer LOS when compared to those with PRU≤230 (median of 2 days vs. 1 day, p=0.049). A positive correlation between HbA1c and PRU was also found (p=0.018). All 8 deaths had abnormal PRU (3 patients with PRU≤178, 5 patients with PRU>230).

Conclusion
Advanced CKD is associated with impairment of platelet inhibition by clopidogrel measured with the VerifyNow P2Y12 Assay. Elevated PRU is associated with worse outcomes. We observed a significant correlation between HbA1c and degree of platelet inhibition.
Abstract 180: Differential Role of Endothelin-1 in Mitral Stenosis and Atrial Fibrillation
Authors: Willoughby Scott R , Schultz Carlee , Kumar Sathesh , Nair Sukesh , Srivastava Alok , Joseph George , Chandy Sunil , John Bobby , Sanders Prashanthan 
Published: July 2021

Background
Chronic atrial stretch due to mitral stenosis is a major substrate for the development of atrial fibrillation (AF). It is well established that rhuematic mitral stenosis and AF are associated with an increased risk of thromboembolic events. Endothelin-1 (ET-1) is a potent vasoconstrictor and modulator of vascular function, and is known to play a role in thrombus formation. We therefore sought to compare ET-1 levels between patients with rheumatic mitral stenosis and AF.

Methods
We measured plasma levels of ET-1 in blood samples from the femoral vein (FV), right atria (RA) and left atria (LA) obtained from 19 patients with rheumatic mitral stenosis, 12 patients with lone AF and 10 subjects with supraventricular tachycardia (reference subjects [REF]). Plasma ET-1 levels were measured by conventional ELISA techniques.

Results
The FV concentrations of ET-1 were significantly higher in rheumatic mitral stenosis patients than in AF patients or REF subjects (Figure). However, there was no significant difference in the concentrations of ET-1 between AF patients and REF subjects. In rheumatic mitral stenosis patients and REF subjects there were no differences in concentrations of ET-1 between the FV, RA and LA. In contrast, ET-1 levels were highest in the femoral vein of AF patients (FV vs RA p<0.03 and FV vs LA p<0.06).

Conclusion
Patients with rheumatic mitral stenosis have significantly higher ET-1 levels than AF patients. These data suggest that ET-1 plays a differential role in the pathophysiology of thrombus formation in mitral stenosis and AF. It highlights the importance of the underlying substrate to the risk of developing thrombus within the atria.
Abstract 183: Differences in Genetic Regulation of Carotid Stenosis and Thickening in Mice
Authors: Gerloff Janice , Genyn Katrien , Lusis Aldons J , Korshunov Vyacheslav A 
Published: July 2021

Introduction
Most clinical and experimental studies are focused on the artery wall using a carotid intima-media thickening (IMT) phenotype. In physiological remodeling increases in IMT are coupled with increased arterial dimensions that preserve arterial blood flow. In contrast, pathological remodeling results in arterial stenosis. The goal of this study was to investigate genetic mechanisms of the carotid stenosis in inbred mice.

Methods and Results

We ligated external and internal branches of the left carotid artery, leaving the occipital artery patent to induce carotid IMT in mice. We evaluated flow-induced carotid remodeling in 9-12 week old males of 30 inbred mouse strains (n=270). Relative reductions in the left carotid blood flow were very similar among the mouse strains (Mean+SD= -86+7%) after two weeks after ligation. All animals were perfusion fixed with formalin and carotid arteries were stained with hematoxylin and eosin. There was less than 2-fold variation in carotid traits in controls. However, ligation resulted in a greater variation of carotid IMT (~6-fold) compared to carotid stenosis (~3-fold). The highest carotid IMT values were in SEA/GnJ, while the lowest IMT was in C3H/HeJ mice. Carotid stenosis was >60% in SEA/GnJ and SJL/J strains. There was significant correlation (R
2
=0.40) between carotid stenosis and IMT across 30 strains. We performed genome-wide association by using Efficient Mixed Model Association method for carotid traits in 30 inbred mice. Comparable numbers of genetic loci were associated with carotid IMT and stenosis after ligation. However, none of these loci overlap between the carotid stenosis and carotid IMT.

Conclusions
We found that major genetic modifiers for carotid stenosis are different from those that control carotid IMT. Our data also suggest that identification of mechanisms that determine carotid stenosis is difficult through studies on the carotid IMT.
Abstract 188: Immobilization Stress Exacerbates Insulin Resistance and Endothelial Dysfunction via Inhibition of Insulin-Stimulated eNOS Activation and via Enhancement of NF-kB Activation by Corticotropin-Releasing Hormone
Authors: Chung Ick-Mo , Kim Hee Young , Lee Youn Jung , Lee Kuy-Sook , Shin Mi-Kyung 
Published: July 2021

Objectives
Psychological stress may contribute to the development of atherosclerosis and insulin resistance. However, its mechanism is poorly understood. We studied if stress induces insulin resistance and endothelial dysfunction, and assessed the role of stress-associated corticotropin-releasing hormone (CRH) in inflammation and insulin signaling pathways.

Methods and Results

Immobilization stress (IS) was applied (2 hr/d) for 14 d to male 8-wk (YI2O: before DM phenotype) and 21-wk (EI2O: DM phenotype) OLETF rats, whereas control groups comprised of rats without IS with same age (YCO and ECO, respectively; n=7~10 for each group). Systolic blood pressure was significantly increased after 14d-IS in YI2O and EI2O, whereas it was not changed in control groups. Acetylcholine-induced, but not nitroprusside-induced, vasorelaxation, measured in superior mesenteric artery, was significantly decreased by 14d IS compared with each control groups, suggesting that IS induced endothelial dysfunction. 14d-IS increased plasma insulin (342.5±6.3 vs 496±51.6 pg/ml) and HOMA-IR (3.1±0.2 vs 4.7±0.5 mmol/LxμIU/mL) in 8-wk OLETF rats (control vs stress, all
p
<0.05). Western blot analysis using thoracic aorta showed 14d-IS increased expression of Rho-associated kinase-1 and p22
phox
subunit of NAD(P)H oxidase compared with control groups. eNOS phosphorylation at Ser
1177
was increased by treatment with insulin (2nM) in cultured HUVEC cells, but this was blocked by pretreatment with CRH (100 nM). On the contrary, an increase in ERK phosphorylation by insulin treatment was further enhanced by CRH pretreatment in HUVEC cells. CRH also induced translocation of NF-kB subunit p65 into nuclear fraction in monocyte cell line U937 cells.

Conclusions
Immobilization stress exacerbates insulin resistance and endothelial dysfunction in a prediabetic animal model at least partly via inhibition of insulin-mediated eNOS activation and via enhancement of inflammation through ERK pathway and NF-kB activation by CRH.
Abstract 194: Increased Monocyte Adhesion and Infiltrative Activity Inhibits Arteriovenous Fistula Maturation for Hemodialysis Access in Patients With End-stage Renal Disease
Authors: Samadzadeh Kiana M , Van Spyk Elyse N , Chun Kevin C , Lee Eugene S 
Published: July 2021

Introduction
Patients with end-stage renal disease (ESRD) require hemodialysis access and arteriovenous fistulas (AVFs) are the preferred method for hemodialysis access. However, 60% of surgically constructed AVFs do not functionally mature and 80% of the reported AVF failures are caused by stenosis at the venous outflow of the fistula. Stenosis is commonly associated with deregulated inflammatory mechanisms and prolonged systemic inflammation is proposed to upregulate monocyte activity within the vessel, affecting vascular remodeling.

Hypothesis
We hypothesize that excessive monocyte interaction with the vessel endothelium from systemic inflammation attenuates AVF maturation and prevents appropriate vascular remodeling. The purpose of this study is to compare monocyte activity through adhesion molecule expression, adhesion to endothelium, and transendothelial migration in patients with a matured AVF versus patients with a failed AVF.

Methods
Peripheral blood was collected from control subjects (n=4) and ESRD patients with failed (n=4) and matured (n=8) AVFs. Endothelial cell adhesion, transendothelial migration, and permeability assays were assessed under static conditions. Flow cytometry was used to determine the presence of monocyte adhesion molecules CD18, CD11a, CD11b, and CD11c.

Results
Monocytes from failed AVF patients exhibited greater expression of CD18 (p= 0.03) and CD11b (p= 0.03) compared to matured AVF patients. Monocytes from failed AVF patients had greater adherence to endothelium in untreated (p= 0.02) conditions compared to matured AVF patients. Monocytes from failed AVF patients had insignificantly greater transendothelial migration towards fMLP (p= 0.2) compared to matured AVF patients. Monocytes from all ESRD patients had more adhesion to endothelium compared to controls (p= 0.01). All ESRD patients had greater transmigration towards fMLP (p= 0.03) compared to controls.

Conclusion
In conclusion, monocytes isolated from patients with failed AVFs have greater CD18/CD11 expression, cell adhesion to the vessel endothelium, and endothelial dysfunction than those from matured AVFs.
Abstract 2: Overexpression of Human Apolipoprotein C-III in Mice Decreases Intestinal Transport of Triglyceride Into Lymph
Authors: Kohan Alison B , Wang Fei , Yang Qing , Huesman Sarah , Dong H. H , Hui David Y , Tso Patrick 
Published: July 2021

INTRODUCTION
Apolipoprotein C-III (apoC-III), synthesized by the liver and intestine, is an inhibitor of LPL-mediated lipolysis and hepatic clearance of triglyceride-rich lipoproteins. ApoC-III overproduction is linked with hypertriglyceridemia and atherosclerosis. ApoC-III may also play an intracellular role in hepatic VLDL assembly/secretion. Little is known about the role of apoC-III in the intestine, although it is secreted on chylomicrons coincident with triglyceride absorption.

HYPOTHESIS
Given that overexpression of apoC-III results in high plasma triglyceride levels, we hypothesized that it might also stimulate intestinal triglyceride transport, thereby exacerbating plasma hypertriglyceridemia in human apoC-III transgenic (h-apoC-III tg) mice.

METHODS
28-30 gram male h-apoC-III tg (on a C57BL/6J background) were fitted with both a mesenteric lymph cannula and a duodenal feeding tube, and received a continuous intraduodenal infusion of triglyceride (6 μmol of 3[H]-Triolein in 0.3ml of phosphate-buffered saline) for 6 hours with hourly lymph samples collected (n=11-12). At the end of the infusion period, luminal and mucosal contents and tissue samples were isolated. An advantage of this lymph fistula model is the ability to sample lymph continuously throughout the triglyceride infusion period while avoiding confounding effects of anesthesia and stomach emptying.

RESULTS
h-apoC-III tg mice had a decrease in lymph flow and a 43% reduction in lymphatic 3[H]-triglyceride transport compared to WT mice. The h-apoC-III tg mice had 10.0±2.3% of the total dose of 3[H]-triglyceride remaining in intestinal lumen; which was significantly higher than the 3.1±0.4% observed in WT mice. Thin layer chromatographic analysis of the luminal contents showed that h-apoC-III tg mice, as opposed to WT controls, had a significantly higher percentage of fatty acid. There were no significant differences in the luminal triglyceride, diglyceride, and monoglyceride composition between groups.

CONCLUSION
Our studies reveal a novel role for apoC-III in decreasing intestinal triglyceride transport distinct from its extracellular roles in plasma on lipoprotein lipase, and its intracellular role in hepatic VLDL synthesis and secretion.