bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 518: Antithrombotic Effects of Apelin: Implication During Metabolic Disorders
Authors: Adam Frederic , Lopez José , Vatier Camille , Turpin Sabrina , Muscat Adeline , Lalou Claude , Valet Phillipe , Khatib Abdel-Majid , Bobe Regis , Feve Bruno , Siegfried Geraldine 
Published: March 2022

Thrombotic risk, that is partly related to a disturbed adipokine/cytokine profile, is strongly increased in obese and type 2 diabetic patients and. Apelin is an adipokine with pleiotropic function and cardiovascular fluid, and energetic homeostasis, and acts through the APJ transmembrane receptor.
In this project, we show for the first time that apelin displays a potent antithrombotic effect The antithrombotic effect is APJ- mediated and requires the proteolytic maturation of apelin. Apelin strongly inhibits thrombin- or collagen- induced platelet aggregation, independently of ADP secretion. It prevents platelet activation and thrombin-activated intracellular signaling pathways.
As a consequence, in mice models, intravenous apelin injection increases tail-bleeding time and delays chemically- induced vessel occlusion and thrombus stabilization.
We also determined that functional APJ is strongly over-expressed in platelet from obese subjects or mice (DIO mice, db/db), but apelin preserved its antithrombotic function during these metabolic disorder conditions.
In conclusion, in this original study, we enlighten a new biological function of apelin that could be considered as a new strategy to reduce the increased risk of thrombosis in patients with metabolic disorders.
Abstract 62: Azathioprine Is Protective in Aneurysm Formation and Progression
Authors: Marinkovic Goran , Hibender Stijntje , de Vries Carlie J , de Waard Vivian 
Published: March 2022

Objective:
An aortic aneurysm is a dilatation of the arterial wall caused by destruction of its integrity, which results in often lethal vessel ruptures. Currently, only surgical treatment is available for patients with growing aortic aneurysms, therefore there is a clinical need to identify drugs to attenuate aneurysm growth. Chronic inflammation is fundamental in aneurysm pathology with excessive leukocyte infiltration. We studied the role of the immunosuppressive drug Azathioprine (AZA) in aneurysm formation.

Methods and Results:
To investigate AZA in aneurysm formation, we used the Angiotensin-II (AngII) aneurysm mouse model. AngII in ApoE
-/-
mice on a Western Type diet resulted in 11/14 (79%) mice with aneurysms, whereas only 3/13 (23%) of the AZA-treated mice developed aneurysms. In the aorta altered signalling downstream of the AngII receptor type 1 was observed on AZA treatment; phosphorylation of Jak2 and JNK was decreased and of p38 and p44/42 was increased. In addition, reduced levels of matrix metalloproteinases (MMP)2 and MMP9 and decreased leukocyte influx was observed in AZA-treated mice.

To study aneurysm progression, AZA treatment was started 10 days after AngII infusion; all mice developed aneurysms, however the aneurysm type was more severe in the control group demonstrating the inhibitory effect of AZA on aneurysm progression.
To delineate the mechanism of AZA protection, we performed experiments with macrophages and endothelial cells in the presence of 6-mercaptopurine (6MP), the active metabolite of AZA. Macrophages produce less IL-12 and IFNgamma and more IL-10 after 6MP incubation and endothelial cells express less CCL5 (Rantes), IL-12 and VCAM1. Adhesion of monocytes to activated endothelial cells is reduced in the presence of 6MP. These data underscore the anti-inflammatory effect of AZA on macrophages and endothelial cells, which may explain the inhibition of aneurysm formation.

Conclusion:
We report a protective effect of AZA in aortic aneurysm initiation and, most importantly, inhibition of progression of the disease. AZA modulates the inflammatory response of macrophages and endothelial cells, inhibits monocyte adhesion to endothelial cells, and modulates AngII signalling in the aortic vessel wall.
Abstract 11: T Cell Functions in a Novel Antigen-specific Experimentally-induced Model of Atherosclerosis
Authors: Tse Harley Y , Welch Kathryn , Van Dusen Hillary , Zhao Xiaoqing , Thummel Ryan , Eitzman Daniel T , Tse Kevin Y , Ley Klaus , Shaw Michael K 
Published: March 2022

Introduction
While it is realized that inflammation plays a key role in the development of atherosclerosis, the underlying mechanism of how T cells, directly or indirectly, trigger and propagate the disease process, is not forthcoming. This is because there is no knowledge of what constitutes an atherogenic T cell and how to isolate it. New and innovative ideas are needed.

Hypothesis
We reason that T cells are antigen specific and identification of the atherogenic antigenic epitopes of an autoantigen should lead us to identification of the atherogenic T cells themselves.

Methods

Since the T cell receptor only recognizes a short peptide of the antigen in association with major histocompatibility complex (MHC) proteins, our focus was directed towards elucidating the peptides that form a ligand with MHC class II proteins and bind to atherogenic T cells. It has been known that oxidized low-density lipoprotein, ApoB100, heat-shock protein 60 and β2 glycoprotein I are the major atherogenic antigens. Because different MHC haplotypes have different binding motifs of peptide sequences and most atherosclerosis experiments are carried out in the H-2
b
ApoE
-/-
mice, we searched for H-2
b
binding motifs along the entire amino acid sequence of murine ApoB100 according to the prediction model of Liu et al.
ApoE

-/-

mice fed Western diet (WD) for 8 weeks were immunized with the identified peptides in CFA. Mice were boosted in 2 weeks and 3 weeks later were sacrificed and the aortic trees were isolated. The extent of atherosclerosis was assessed via en face staining of the aortic samples with Oil Red O.

Results
We identified eighteen such peptides, six of which were selected for synthesis. Two of the peptides, peptide6 (P6) and peptide3 (P3) induced strong proliferative responses in immunized mice, but only P6 was atherogenic in enhancing development of atherosclerosis in WD-fed and P6-immunized mice. The proliferative T cells were of the CD4 type, producing IL-17, IFNγ as well as IL-10 and IL-13. T cell clones were derived from P6-primed mice and adoptive transfer of these clones into WD-fed recipients also showed enhanced atherosclerosis.

Conclusions
Our identification of a T cell epitope of ApoB100 allows cloning of a population of peptide-specific atherogenic T cells.
Abstract 114: Correlation of Specific HDL Subspecies with Arterial Stiffness in Youth with Type 2 Diabetes
Authors: Gordon Scott M , Lu Jason , Dolan Lawrence , Urbina Elaine , Shah Amy , Davidson W. Sean 
Published: March 2022

Human epidemiological studies demonstrate that increased HDL cholesterol (HDL-C) concentrations are associated with a decreased risk of cardiovascular disease. However, recent drug therapies designed to raise plasma HDL-C concentrations have failed to reduce cardiovascular events. These findings suggest that the cardio-protective effects of HDL may lie in specific HDL subspecies and not in the HDL-C number. Thus, we sought to define the composition of HDL in adolescents with T2D and determine whether specific HDL subspecies are associated with early markers of arterial disease.
Youth with T2D (n=10) and two control groups lean (n=9) and obese (n=11) adolescents were recruited in a cross sectional study. Plasma was separated into 18 fractions using gel filtration chromatography. Lipid associated proteins were then isolated and identified using mass spectrometry. Concurrently, arterial thickness and stiffness measures including common/bulb/internal carotid intima media thickness (IMT) and pulse wave velocity (PWV) were measured.
Compared to lean and obese controls, youth with T2D exhibited decreased phospholipid content in fractions containing large HDL subspecies that was inversely associated with pulse wave velocity (p<0.001). No association between HDL-C and pulse wave velocity was seen. Proteomic analysis of the HDL sized fractions demonstrated decreases in 17 of 45 identified proteins in the T2D group compared to lean youth. The most striking protein decreases occurred in apolipoprotein (apo) A-1, apoC-I, apoE and paraoxonase-1 (p<0.05) in fractions associated with large HDL particles.
Our data demonstrate early changes in the lipid and protein compositions of specific HDL subspecies in adolescents with T2D that are related to early markers of arterial disease. These findings suggest that analyzing the composition of HDL, rather than HDL-C, may be useful in assessing cardiovascular risk in this population.
Abstract 117: Does Lipoprotein (a) Impact the Classification of Intermediate to High Risk Patients using Reynold’s Risk Score
Authors: Low Li Shien , Gout Marcel , Siracusa Mary , Zenebe Wondwossen , Parikh Devang , Kazlauskaite Rasa , Lundberg Gina , Doukky Rami , Braun Lynne , Volgman Annabelle 
Published: March 2022

Introduction
Elevated lipoprotein (a) (Lpa) has been linked repeatedly with cardiovascular disease (CVD) events. Two models of the Reynold’s Risk Score (RRS) A & B were validated to be effective predictors of CVD events. Lpa was included in RRS A but was excluded in RRS B. We sought to determine the proportion of patients (pts) that are reclassified into a different risk category utilizing RRS A instead of the simplified RRS B.

Methods

Female pts with Lpa and data for RRS seen from 2006-12 at the Heart Centers for Women at RUMC and Emory Healthcare were included. Charts were reviewed for pt characteristics and biomarkers using Berkeley Heart Lab including: Total, LDL, and HDL cholesterol, triglycerides, ApoB, Lpa, HS-CRP, HgB A
1
c and history of hypertension, diabetes, current smoking, family history and blood pressure. HDL was substituted for ApoA
1
in all cases in RRS A. RRS A and B were calculated. The proportions of pts within different risk strata were compared between the two models.

Results
Of 604 women, 502 of them age 45 to 80 years old were included in this analysis, because RRS has been validated only in this age group. The table summarizes that a high proportion of women were reclassified into different risk strata using RRS B score.

Discussion
The addition of Lpa reclassifies up to 81% of pts’ risk categories. Given that model A was the better fitting model, we propose the incorporation of Lpa in women whose risk is > 5% as determined by the simplified RRS B. Treatment implications may impact cardiovascular outcomes.
Abstract 129: Investigation of Atherosclerosis in Association with Arthritic Inflammation
Authors: Bäcklund Alexandra , Ria Massimiliano , Chernogubova Ekaterina , Ketelhuth Daniel FJ , Holmdahl Rikard , Hansson Göran K. , Hamsten Anders 
Published: March 2022

Background and Aims
It is well established that patients with Rheumatoid Arthritis (RA) have a higher risk of developing coronary artery disease (CAD). However, it is unclear how the inflammatory process affects atherosclerosis and what specific factors are involved. In this study, we investigated the effect of the pro-atherogenic factor hyperlipidaemia on arthritis incidence and severity. Simultaneously, we have investigated the mutation of the neutrophil cytosolic factor 1 (Ncf-1), a known genetic factor that promotes arthritis susceptibility, and MHCII H-2q on atherosclerosis development.

Results
We observed that diet-induced hyperlipidaemia prior to induction of collagen induced arthritis (CIA) protected mice against the disease while genetically hyperlipidemic without the use of diet, Ldlr-/- x human ApoB100 transgenic (Ldlr-/-hApoBtg), were equally susceptible to CIA compared to their heterozygous littermates. Next, we investigated Ncf-1 mutation on Ldlr-/-hApoBtg mice. Surprisingly, despite the increased inflammatory/arthritic phenotype induced by Ncf-1 mutation, no difference in the atherosclerotic lesion size was observed.

Conclusions
Our data shows that hyperlipidaemia-induced by diet have substantial effects on arthritis susceptibility, which in turn differs from hyperlipidaemia acquired on birth due to genetic alterations. By developing a model carrying pro-arthritogenic factors, MHCII H-2q and Ncf-1 mutation, as well as the pro-atherosclerotic factors, Ldlr-/- and hApoBtg, we have established a new model where both arthritis and atherosclerosis are present. These mice will be used to further characterize the impact of systemic inflammation in the form of arthritis in the atherosclerotic process and vice versa.
Abstract 130: Platelet Rap1 Signaling, Mediated by CalDAG-GEFI and P2Y12, Contributes to Atherosclerotic Lesion Development in Mice
Authors: Boulaftali Yacine , Owens A.Phillip , Beale Ashley , Piatt Raymond , Andre Patrick , Conley Pamela B. , Mackman Nigel , Bergmeier Wolfgang 
Published: March 2022

Background and Objective
The development and progression of atherosclerotic lesions is mediated by various blood cell types, including platelets and neutrophils. We recently identified CalDAG-GEFI (CDGI) as a critical component of integrin-mediated adhesion of platelets and neutrophils at sites of vascular injury. In platelets, signaling by CDGI mediates the early activation of Rap1, while receptor for ADP, P2Y12, the target of the clinically used drug Plavix, is required for sustained Rap1 activation and thrombus stability. In this study, we evaluated lesion formation in atherosclerosis-prone low-density lipoprotein receptor deficient (Ldlr-/-) mice lacking CDGI and/or P2Y12 in hematopoietic cells.

Methods and Results
Ldlr-/- mice were irradiated and reconstituted with bone-marrow from wild-type (WT), CalDAG-GEFI-/- (CdgI), P2y12-/-, or CdgI-/- P2y12-/- (DKO) mice. Reconstituted mice were fed a fat and cholesterol enriched diet (21% fat, 0.2% cholesterol) for 12 weeks, ad libitum. Atherosclerotic lesions in the aortic sinus of Ldlr-/-;CdgI-/- chimeras were 42% smaller than those in Ldlr-/-;WT controls (0.18 ± 0.02 mm2 vs 0.31 ± 0.05 mm2, respectively; n = 13 each group, p < 0.001). Lesions in Ldlr-/-;P2y12-/- chimeras were also significantly smaller compared to controls (0.22 ± 0.10 mm2; n = 13, p < 0.05). Lesions in Ldlr-/-;DKO were reduced by 48% compared to WT controls (0.16 ± 0.02 mm2; n = 13, p < 0.001 ), but they were not statistically different from Ldlr-/-;CdgI-/- chimeras. Platelet adhesion and activation on collagen under flow was markedly impaired in Ldlr-/-;CdgI-/- and Ldlr-/-;DKO blood, but only partially impaired in Ldlr-/-;P2y12-/- blood. Importantly, firm neutrophil adhesion to collagen-bound platelets was significantly reduced in Ldlr-/-;CdgI-/- and Ldlr-/-;DKO blood, but not in Ldlr-/-;P2y12-/- blood. Total cholesterol and triglyceride levels were similar among groups.

Conclusion
Our findings reveal a critical role for CDGI and P2Y12, and Rap1-dependent platelet activation, in promoting atherosclerotic lesion development in hypercholesterolemic mice. Further studies are required to determine if the observed protection in Ldlr-/-;CdgI-/- chimeras is due to impaired neutrophil function.
Abstract 131: Alphavbeta3 Integrins Mediate Shear Stress-Induced Inflammation and Early Atherogenesis
Authors: Chen Jie , Green Jonette , McInnis Marshall , Traylor James G. , Mazar Andrew P. , Orr A. Wayne 
Published: March 2022

Rational
The frictional shear stress generated by blood flow activates integrins on the endothelial cell surface, and signaling downstream of newly activated integrins regulates several flow-induced responses including inflammation and permeability. Signaling through transitional matrix binding integrins (α5β1, αvβ3 and αvβ5) drives shear stress-induced NF-κB activation and proinflammatory gene expression; however the specific contribution of each of these integrins remains unclear.

Objective
To address which transitional matrix-binding integrin mediates shear stress-induced endothelial cell.

Methods and Results
We now show that the small molecule αv integrin inhibitor S247, but not the α5 inhibitor ATN-161, abolished flow-induced proinflammatory signaling (PAK, NF-κB). Blocking αv expression using siRNA similarly prevents flow-induced activation of PAK and NF-κB, whereas siRNA-mediated knock-down of α5 did not. Furthermore, αv and β3 knockdown but not α5 and β5 knockdown inhibited flow-induced ICAM-1 and VCAM-1 expression (both mRNA and protein) following either short term (5 hr) laminar and long term oscillatory (24 hr) shear stress, indicating αvβ3 is the mediator for flow induced endothelial cell inflammation. In contrast, αv knockdown did not affect TNFα-induced ICAM-1 and VCAM-1 expression, suggesting the anti-inflammatory effect of αv inhibition is specific to shear stress. Integrin inhibition did not affect all shear stress responses, as neither α5 nor αv siRNA affected shear stress-induced extracellular-signal regulated kinase (ERK1/2) activation. Lastly, inhibiting αv integrins using the small molecule inhibitor S247 reduces atherosclerotic plaque formation in ApoE knockout mice.

Conclusion

Taken together, these studies suggest that αvβ3 integrins mediate shear stress-induced proinflammatory responses associated with the transitional matrix
in vitro
and early atherosclerotic plaque formation
in vivo
.
Abstract 136: Quercetin Intake With Exercise Modulate Adipose Response in Mice Fed Atherogenic Diet
Authors: Garelnabi Mahdi , Mahini Halleh , Massie Melissa , Cook Carla , Santanam Nalini 
Published: March 2022

Adipose tissue is shown to influence atherosclerotic plaque formation and contribute to cardiovascular disease. Recent studies have focused on the potential role of adipose tissue physiopathology on several metabolic diseases.

Aims and Objectives
In the current study we hypothesized that the combined action of quercetin and exercise will promote the releases of adipose anti-atherogenic metabolites and contribute to the reduction of the plaque formation.

Study Design
C57BL6 LDL -/- mice fed atherogenic diet (40) was divided into four groups (10 each). These groups are as follows: Control mice, left untreated; control quercetin group, orally supplied with 100 μg/day of quercetin without exercising; exercise group without quercetin, and exercise group with quercetin supplements. The exercise groups were run on a treadmill for 30 minutes, 15m/m/ 5 days/week for 30 days. All animals were on atherogenic diet. At the end of the month of treatment, mice were sacrificed, and adipose tissue gene expressions for selected genes were analyzed.

Results and Conclusion
We previously reported that mice on quercetin and exercise have significant (P<0.001) drop in body weigh accompanied with a 78% drop in the atherosclerotic plaque development in exercising groups. In the current abstract we investigated whether the drop in weight is mediated through an adipose tissue based mechanism. The adipose gene expression studies have shown significant (P<0.0001) up regulation of PPARg in exercised mice compared to the control and quercetin fed group, and PPARg also increased with exercise and quercetin intake although these changes were not significant. Adiponectin on the other hand elevated with exercise or quercetin intake alone and there was no appreciable changes with the combination of exercise and quercetin intake compared to control. Exercise; quercetin or the combination increased SREBP-1; however, interestingly quercetin intake with exercise significantly increased leptin up regulation. Circulating leptin levels are known to correlate with white adipose tissue mass. This finding brings an amazing perspective to the role of antioxidants taken with exercise which need further investigation to establish its mechanism(s) that modulate adipose metabolism.
Abstract 138: Treatment of Atherosclerosis by Systemic Protease Inhibition
Authors: Hu Jie Hong , Touch Phanith , Zhang Jingwan , Liu Shihui , Lund Ida K , Høyer-Hansen Gunilla , Dichek David A 
Published: March 2022

Background

Elevated activity of urokinase plasminogen activator (uPA) and matrix metalloproteases (MMPs) in human arteries is associated with accelerated atherosclerosis (athero), aneurysms, and plaque rupture.
Apoe
-null mice with macrophage-targeted uPA overexpression (SR-uPA mice) have elevated vascular uPA and MMP activity, accelerated athero, dilated aortic roots, and increased histologic features of plaque rupture. SR-uPA mice are therefore a useful experimental setting for beginning to investigate whether inhibition of uPA or MMPs can prevent athero progression, aortic dilation, and plaque rupture.

Hypothesis
Treatment with a murine monoclonal antibody inhibiting mouse uPA (mU1), or a limited-spectrum synthetic MMP inhibitor (XL784) will reduce athero in SR-uPA mice.

Methods
SR-uPA mice were fed a high-fat diet for 10 wk beginning at 5 - 6 wk of age. Fat-fed mice were injected with mU1 or control antibody twice per wk (for 10 wk), or were given either XL784 (125, 250, or 500 mg/kg) or vehicle by daily oral gavage. Mice were then anesthetized, formalin-perfused, and athero was measured in isolated aortic roots and pinned aortas. Groups were compared by t-test and ANOVA.

Results

None of the treatments altered peripheral blood monocyte counts or plasma cholesterol. mU1 reduced aortic root intimal lesion area by 20% (
P
< 0.05) and aortic root circumference by 12% (
P
= 0.01). All 3 doses of XL784 significantly decreased oil-red O-positive lesion area (36 - 42%;
P
< 0.05 for all). All XL784 doses also reduced aortic root intimal lesion area (22 - 29%;
P
< 0.05 for low dose only). The highest XL784 dose also reduced total macrophage-positive lesion area (33%;
P
< 0.05). All XL784 doses yielded trends towards decreased aortic root circumference (5 - 10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage.

Conclusions
In SR-uPA mice, pharmacologic inhibition of either uPA or selected MMPs significantly decreased aortic root athero and limited aortic dilation. Differential effects of both agents on aortic root versus surface athero suggest prevention of athero progression rather than initiation. These approaches to protease inhibition show promise for preventing the progression and complications of established athero.
Abstract 148: AGES, Receptor for Advanced Glycation End Products (RAGE), Reverse Transmigration of Macrophages & Polarization
Authors: Senatus Laura M , Shen Xiaoping , Zou Yu Shan , Li Huilin , Daffu Gurdip , Rosario Rosa , Schmidt Ann Marie 
Published: March 2022

Cellular migration is fundamental processes linked to diverse pathological states including atherosclerosis and diabetes. RAGE is a multiligand cell surface macromolecule, which binds ligands such as advanced glycation endproducts (AGEs) in diseased settings such as atherosclerosis. We tested the hypothesis that RAGE contributes to impaired regression of diabetic atherosclerosis by suppression of reverse transmigration of macrophages in an AGE-enriched environment. We performed our studies in vitro, a reverse transmigration assay, using primary murine aortic endothelial cells from wild-type C57BL6 mice and wild-type or RAGE deficient primary bone marrow derived macrophages (BMDMs). Our data is shown in the table.
We evaluate if the expression of RAGE modulates influx and/or egress of macrophages from the atherosclerotic lesions in the non-diabetic and diabetic states. We used a monocyte bead-tracking model in an aorta transplantation study with LDL-/-diabetic mice fed high-fat diet as a baseline (donors), and non-diabetic RAGE-/- or WT mice as recipient. Migration patterns evaluated by labeled monocytes, showed a decrease in bead number in RKO recipients (23±0.05 p<0.05) compared to WT (30±0.05 p<0.05) indicating emigration of monocyte- derived cells from the plaque in the diabetic state.
We also tested if RAGE plays roles in macrophage polarization. AGEs-RAGE axis increases M1 polarization (MCP 1, TNF alpha, iNos, p<0.05) and suppresses M2 polarization (Arg1, IL-10, p<0.05) in a manner prevented by deletion of RAGE in BMDMs. Our studies suggest AGEs-RAGE axis action delays reverse transmigration of macrophages and augments pro-inflammatory gene expression.