bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 239: Dpp-4 Inhibitor Alogliptin Prevents Abdominal Aortic Aneurysm Formation and Development in Rat Model
Authors: Morimoto Keisuke , Bao Wulan , Yu Zhenhai , Jie Yu , Sasaki Naoto , Yamashita Tomoya , Hirata Kenichi , Okita Yutaka , Okada Kenji 
Published: March 2022

Objective
Dipeptidyl peptidase-4 (DPP-4) inhibitor, a novel anti-diabetic drug, has been proved to have a cardioprotective effect on ischemia-reperfusion injury through an antioxidant effect. Although we reported reactive oxygen spices (ROS) play a crucial role in AAA formation and development, the effect of DPP-4 inhibitor on AAA has not been investigated. In this study, we examined the effect of DPP-4 inhibitor alogliptin on experimental AAA rat model.

Methods
An AAA model induced with intraluminal elastase and extraluminal calcium chloride was created using 48 rats. Thirty-six rats were divided into 3 groups; a low dose (group LD; 1mg/kg/day), high-dose (group HD;3mg/kg/day), and control (group C; pure water). Alogliptin was administered by gastric gavage once per day beginning 3 days before surgery. The remaining 12 rats received a delayed alogliptin administration (group DA-LD; 1mg/kg/day, group DA-HD; 3mg/kg), starting on day 7 after aneurysm preparation up to 28 days. On day 7, ROS expression was semi-quantified by dihydroethidium staining and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining. Histopathological examination was performed on day 28, and AAA dilatation ratio was calculated.

Results
On day 7, ROS expression were reduced (4.6±0.6 in group C, 2.7±0.3 in group LD, 1.7±0.5 in group HD; p<0.001) and there were fewer 8-OHdG positive cells in alogliptin treated samples (138.1±7.4 in group C, 102.5±4.5 in group LD, 66.1±4.5 in group HD; p<0.001). The treatment reduced messenger RNA expression and activity of matrix metallo-proteinases 2 and 9 in aneurysm walls. On day 28, aortic walls in group LD and HD were less dilated than those in group C (199.2±11.8 % in group C, 159.6±2.8 % in group LD, 147.1±1.9 % in group HD; p<0.02). Delayed alogliptin administration prevented further aneurysm dilatation compared with the aortic walls in group C at day 7 (158.9±8.5 % in group C at day 7, 160.1±14.3 % in group DA-LD, 155.1±2.6 % in group DA-HD; n.s.).

Conclusion
DPP-4 inhibitor alogliptin treatment starting on day 7 after aneurysm preparation completely inhibited aneurysm development. Alogliptin could be effective pharmaceutical agent against AAA in clinical practice.
Abstract 242: Novel Therapeutic Approach to Abdominal Aortic Aneurysm through the Inhibition of Osteoclastogenesis
Authors: Takei Yuichiro , Kurosawa Koji , Yamanouchi Dai 
Published: March 2022

Arterial calcification, which mainly consists of calcium phosphate (CaPO4) crystals, has been proven to be an organized process, just like the processes seen in bone. Osteoclast-like cells (OCLCs), which are derived from the monocyte/macrophage lineage, dissolve extracellular matrices with proteases. Although OCLCs have been reported to exist in the calcified artery, their role in abdominal aortic aneurysm (AAA) hasn’t previously been explored and was investigated in this work.
First, we obtained human aortic tissues from patients who had undergone surgical repair for AAA and aortic stenotic disease (N = 5). Calcifications were abundant in both groups. However, multinucleated cells positive for osteoclast markers (enzymatic tartrate-resistant acid phosphatase staining, calcitonin receptor, vitronectin receptor, and CD68) were identified only in AAA tissues. We then checked the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG), key regulators of osteoclastogenesis, and TNFα, a pro-inflammatory cytokine. Immunohistochemical analysis showed upregulation of TNFα but not RANKL/OPG in AAA compared with stenosis. To mimic the pathogenic conditions of aneurysm and stenotic disease in vitro, we stimulated macrophages (RAW 264.7 cell line) with CaPO4 crystals with or without TNFα (100 ng/ml). Aneurysmal conditions (CaPO4 with TNFα) induced a significantly greater number of OCLCs than stenotic conditions (CaPO4 without TNFα) or control conditions (TNFα only, P < 0.01), with higher MMP-9 secretion after 5 days. Furthermore, inhibition of OCLCs with anti-TNFα (10 μg/ml, locally) or bisphosphonate (zoledronate, 100 μg/kg, i.v.) inhibited mouse CaPO4 aneurysm and osteoclastogenesis (P < 0.01, N = 5). Finally, we confirmed a spatial correlation between fluorescein-conjugated bisphosphonate and OCLCs in the CaPO4-treated artery.
In conclusion, we have demonstrated the existence of OCLCs in AAA and therapeutic effects of OCLCs inhibition on aneurysms. Our in vitro data showed that TNFα with CaPO4 induces osteoclastogenesis. These data suggest that inflammation in the calcified artery initiates osteoclastogenesis, which may be used to differentiate between stenotic and aneurysmal degeneration.
Abstract 245: Metabolic Syndrome and Common Carotid Artery Remodeling: Study of Women’s Health Across the Nation
Authors: Asubonteng Julius O , Barinas-Mitchell Emma J , Wisniewski Stephen R , Selzer Faith M 
Published: March 2022

Objective
The metabolic syndrome (MetS) is linked to a higher risk of cardiovascular disease (CVD) events, including stroke. Measures of maladaptive carotid artery remodeling such as greater common carotid artery (CCA) intima-media thickness (IMT), and wider adventitial diameter (AD) are more prevalent among older women, varies by race/ethnicity and is predictive of stroke, however, data are lacking in women during the menopausal transition. Thus, we hypothesized more maladaptive carotid remodeling among MetS than those without MetS by race/ethnicity.

Methods
Study of Women’s Health Across the Nation (SWAN) participants, free of clinical CVD and with IMT and AD data at the 12th annual visit were evaluated. Lumen diameter (LD), circumferential wall stress (CWS) and circumferential wall tension (CWT) were calculated. Multivariable linear regressions were used to investigate the relationship between MetS and CCA parameters in all women and by race/ethnicity. Covariates included were age, height, site, LDL-c, education, medication use, menopause status and smoking.

Results
A total of 1183 women (41.3% MetS; 96.9% Postmenopausal; 52.1% Caucasian, 27.6% African American, 14.6% Chinese, 5.8% Hispanic) from 6 sites across the USA, aged 60.1±2.7 years old at visit 12 were included. MetS was associated with a larger LD (β(SE)): 0.222(0.033) mm, P <0.0001; AD (0.317(0.038)) mm, P <.0001; IMT(0.047(0.006)) mm, P <.0001; CWS (2.51(0.938)) kPa, P <.0077; CWT (5.53(0.637) kPa, P <.0001), after adjusting for covariates. Compared to Caucasians, LD was greater in both African American and Chinese ( (0.130 (0.040) mm, P <.0001; 0.292(0.064) mm, P<.0001, respectively), AD was greater in African American ((0.236(0.046) mm, P <.0001) and Chinese ((0.331(0.073) mm, P <.0001), a thicker IMT((0.053(0.008) mm, P <.0001), CWT was greater for African American and Chinese ((4.83(0.776) kPa, P <.0001; 3.18(1.22) kPa, P =0.0093).

Conclusion
MetS is associated with maladaptive remodeling of the CCA, as evidenced by larger AD, LD, IMT and CWT. Importantly, the association between MetS and CCA remodeling varies between race/ethnicity, which could partially explain differences in stroke rates by race.
Abstract 26: 12-Lipoxygenase is an Essential Regulator of Fatty Acid Protection Against Platelet Activation and Thrombosis
Authors: Yeung Jennifer , Vesci Joanne , Holman Theodore R , Holinstat Michael 
Published: March 2022

Introduction
Human platelet-type 12-lipoxygenase (12-LOX) has recently been shown to play an important role in regulation of platelet function by reacting with arachidonic acid (AA). It is possible that a number of other fatty acids present on the platelet surface are oxidized by 12-LOX. Identifying novel bioactive metabolites which regulate platelet function are essential for understanding the role of 12-LOX in regulation of thrombosis, vessel occlusion, and stroke.

Objectives
We sought to characterize the substrate specificity of 12-LOX against several polyunsaturated fatty acids (PUFAs) in vitro, ex vivo, and in vivo and determine if PUFA metabolites act as endogenous regulators of platelet activation.

Methods
Metabolite production was measured in vitro by assessing which PUFAs are oxidized by 12-LOX to form bioactive metabolites. These metabolites were further characterized for anti-platelet properties in platelets ex vivo. Finally, using wild-type and 12-LOX-deficient mouse models, the importance of 12-LOX in regulating the protective effects of these PUFAs was assessed in vivo.

Results
A number of PUFAs were found to be oxidized by 12-LOX in vitro. The bioactive lipid products resulting from 12-LOX oxidation of DGLA in particular, 12-(S)-hydroperoxy-8- Z, 10E, 14Z-eicosatrienoic acid [12(S)-HPETrE], and its reduced product, 12(S)-HETrE, resulted in significant attenuation of agonist-mediated platelet aggregation, granule secretion, α IIbβ3 activation, Rap1 activation, and clot retraction. Treatment with DGLA similarly inhibited platelet activation as well as platelet clot retraction. Blocking 12-LOX rescued normal platelet activity. Finally, mice fed a DGLA-enriched diet showed increased bleeding and decreased platelet activity. However, mice deficient in 12-LOX were resistant to DGLA-induced attenuation of platelet activation but not direct application of 12-HETrE.

Conclusions
These observations support our hypothesis that the overall effect of 12-LOX oxidation of fatty acids in the platelet is dependent on the fatty acid substrates available at the platelet membrane. DGLA and its metabolite 12-HETrE may help explain the protective effect of PUFAs on cardiovascular function.
Abstract 265: Perioperative Silent Myocardial Ischemia, the Use of Blood Transfusions and Their Associations With Long-Term Mortality Following Peripheral Vascular Surgery
Authors: Schneider Gabriel , Rockman Caron , Riegel Daniel , Berger Jeffrey 
Published: March 2022

Objective
Thrombotic and bleeding complications during the perioperative period are a major concern during the postoperative period. However, the relationship between perioperative myocardial necrosis and major bleeding with long-term mortality is uncertain.

Methods
In a retrospective study, we analyzed data from 289 consecutive patients during a one-year period between 2009-2010 who underwent open major vascular surgery (carotid endarterectomy, above/below knee amputation, open aneurysm repair, extremity bypass, and embolectomy). Myocardial necrosis was defined as any cardiac troponin T value ≥ 0.1 ng/ml and major bleeding was defined as requiring ≥2 units of blood within 24 hours of the operation. Lower threshold cutoffs (troponin >0.04 ng/ml and any transfusion) were also investigated. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression.

Results
During a mean follow-up period of 1.8 years, there were 46 deaths (15.9%). Myocardial necrosis and major bleeding occurred in 25.2% and 14.9% of subjects, respectively. After adjustment for age, sex, smoking, hypertension, diabetes and coronary artery disease, both myocardial necrosis (OR 4.24, 95% CI 1.82-9.87) and major bleeding (OR 2.56, 95% CI 1.28-5.46) were associated with long-term death. Similarly, lower threshold cutoffs of troponin >0.04 ng/ml and any transfusion independently predicted a 6.27-fold and a 6.44-fold increase in long-term mortality (p<0.001 for both).

Conclusions
Perioperative myocardial necrosis and major bleeding, even at low cutoff levels, are independent and complementary predictors of long-term mortality following major vascular surgery.
Abstract 272: Epidermal Growth Factor Dependent Collagen Loss in Human Carotid Plaques is Mediated by Matrix Metalloproteinase-9
Authors: Rao Velidi H , Kansal Vikash , Hunter William J , Agrawal Devendra K 
Published: March 2022

Aims
Atherogenesis is a chronic progressive process that develops over several decades. Changes in the structure and composition of extracellular matrix (ECM) play an important role in the process of atherosclerosis. Matrix metalloproteinases (MMPs) and growth factors present in atherosclerotic human plaques could be related to plaque remodeling and increased risk for plaque destabilization and rupture.

Hypothesis
Selective inhibition of elevated MMP-9 and epidermal growth factor receptor (EGFR) increases fibrillar collagens (Type I and III) in vascular smooth muscle cells (VSMCs) from symptomatic (S) and asymptomatic (AS) patients with carotid stenosis.

Methods and results
Cultured human VSMCs from both AS and S patients were treated with or without epidermal growth factor (EGF). The proteolytic activity of MMP-9 and MMP-2 was quantified by gelatin zymography. The mRNA transcripts of MMP-9, MMP-1, EGFR and collagen types I (COL1A1 and COL1A2) and III (COL3A1) were analyzed by qPCR. EGF treatment significantly increased MMP-9 activity and mRNA transcripts for MMP-9, MMP-1and EGFR, while mRNA transcripts for collagen types I and III were decreased in both AS and S groups. Collagen type I and type III mRNA transcripts were significantly decreased in symptomatic VSMCs compared to cells from AS. Inhibition of EGFR with AG1478 and MMP-9 using small molecule inhibitor and transfection with MMP-9 siRNA decreased the activity and mRNA expression of MMP-9 and increased mRNA transcripts of collagen I and III in EGF treated VSMCs.

Conclusion
These results reveal a novel mechanism by which MMP-9 induced by EGFR activation could be a leading cause of plaque instability in patients with carotid stenosis; and the selective blockade of EGFR and MMP-9 may be a novel strategy and a promising target for treating human unstable and vulnerable plaques.
Abstract 275: Cholesterol Efflux Capacity is Inversely Associated with Severity of Carotid Atherosclerosis and Increases with Time Since Cerebrovascular Event
Authors: Doonan Robert-James , Hafiane Anouar , Genest Jacques , Daskalopoulou Stella S 
Published: March 2022

Introduction
HDL is thought to exert its atheroprotective role by promoting cholesterol efflux from lipid-laden macrophages. Cholesterol efflux capacity (CEC) has been shown to be inversely associated with carotid intima-media thickness and presence of coronary artery disease. We assessed the hypothesis that CEC is associated with severity of carotid atherosclerosis and with cerebrovascular symptomatology.

Methods
Symptomatic (n=114) and asymptomatic (n=41) patients with carotid stenosis were recruited from Vascular Surgery at the Royal Victoria and Jewish General hospitals, Montreal, Canada. Carotid Doppler ultrasound was performed and stenosis (50-79%, 80-99%) was graded according to velocities. Detailed information on symptomatology obtained. A blood sample was collected on the day of the ultrasound; HDL was obtained by polyethylene glycol precipitation after depletion of apoB-containing lipoproteins. CEC was determined by incubating HDL in cAMP-stimulated J774 mouse peritoneal macrophages for 6 hours. Specific cholesterol efflux was obtained by subtracting total efflux from efflux in non-cAMP stimulated cells. Differences in CEC were assessed using linear regression according to 1) stenosis, 2) symotomatology and, 3) timing of symptomatology.

Results
Compared to patients with 50-79% stenosis (n=31), patients with 80-99% stenosis (n=124) had significantly decreased CEC (beta=-2.23, P=0.04) after adjustment for age, sex, apoAI, and systolic BP. CEC was not significantly different between symptomatic or asymptomatic patients. However, in symptomatic patients CEC increased with increasing time since cerebrovascular event. Specifically, compared to 0-30 days (n=72), CEC was non-significantly increased 31-90 days since event (n=31, beta=1.64, P=NS), while increased significantly ≥ 90 days since event (n=11, beta=4.48, P=0.01), after adjustment as described above.

Conclusion
These results suggest that CEC is inversely associated with severity of carotid stenosis and that CEC increases with increasing time since symptomatic event. This may be related to remodeling of HDL during the acute phase reaction after a recent ischemic event.
Abstract 306: Transfected Early Growth Response Gene-1 DNA Enzyme Attenuates Autogenous Vein Graft Intimal Hyperplasia in vivo
Authors: Liu Chengwei , Wang Shi , Zhang Xuesong , Peng Yu , Tao Ming , Ozaki Charles Keith , Wang Shuqing 
Published: March 2022

Introduction
Early growth response gene-1 (Erg-1) functions centrally in cell proliferation. We hypothesized that introduction of a novel Egr-1 DNA enzyme (EDRz) via liposomes into the vein graft would attenuate occlusive SMC proliferation and intimal hyperplasia.

Methods

Rat jugular vein was anastomosed to the infrarenal abdominal aorta end-to-end. EDRz (n=90) was applied to the graft vein adventitia (no therapy control; n=90). Animals were harvested at 1, 2, and 6hr, and 1, 3, 7, 14, 28, and 42d (10 EDRz/10 control per time point). Analyses included light microscopy (morphology), fluorescence (EDRz transfection), RT-PCR and
in situ
hybridization (Egr-1 mRNA), and Western blot and immunohistochemistry (Egr-1 protein).

Results
EDRz localized to the vein graft media early; Egr-1 protein was in medial SMCs, monocytes, and ECs; treated grafts had no detectable Egr-1 RNA or protein by 7d. VSMC proliferation (p<0.01 from 3-42d) and intimal thickness were attenuated by EDRz (p<0.01 from 7-42d; Fig ).

Conclusions
EDRz reduces Egr-1 expression, SMC proliferation, and intimal hyperplasia in autogenous vein grafts. EDRz offers a novel approach to enhance vein graft durability.
Figure. The result of thickness of intimal hyperplasia in vein graft and EDRz transfection after
1
Abstract 316: A Superantigen Whole Blood Challenge Test for the Quantification of Immuno-inflammation in Early Phase Drug Development
Authors: van Poelgeest Eveline , Burggraaf Jacobus , Malone Karen , Kluft Cornelis , Moerland Matthijs 
Published: March 2022

Development of immune-modulating drugs is challenging as assessment of intended pharmacology in healthy volunteers is difficult. Commonly, ex-vivo LPS challenges of whole blood or isolated cells are applied. However, the applicability of the LPS challenge is limited as LPS primarily stimulates germ-line encoded innate-immune TLR4-receptors, and thus does not allow monitoring of pharmacological modulation of the adaptive immune compartment. We explored an alternative whole blood challenge, inducing lymphocyte-driven inflammation by the superantigen staphylococcal enterotoxin B (SEB), and compared this to LPS. Further validation was performed by assessing the inhibitory effects of different immune-modulating compounds (MAP kinase inhibitors, calcitriol, methotrexate, protein kinase C, doxycycline, simvastatin), allowing discrimination between effects on monocytes and lymphocytes.
SEB induction resulted in the release of a cytokine panel that well-resembled cytokine release observed after physiological lymphocyte stimulation, with clear induction of IL-2, IFN-γ, TNF- α, IL-10 and GM-CSF. Based on TNF-α and IL-2 release, SEB’s maximal effect was reached at 100 ng/mL. Whereas inter-individual variability in EC50 was relatively small for LPS (0.32±0.10 ng/mL), for SEB inter-subject variability was distinctly higher (62±54 ng/mL). MAP kinase inhibitors and calcitriol were effective in inhibiting SEB-induced TNF-α and IL-2 release, demonstrating an inhibitory effect on the monocyte and/or lymphocyte. Importantly, whereas methotrexate, doxycycline, and simvastatin did not affect SEB-induced TNF-α release, a clear inhibiting effect on SEB-induced IL-2 release was observed, implying a direct action of these compounds on the lymphocyte.
These data demonstrate that the SEB challenge can be used to estimate the immune-modulating effects of compounds directly acting on the T-lymphocyte population. As such, the whole blood SEB challenge is a useful translational tool in early drug development, especially since immune-inflammation is a target in the development of new treatment modalities for currently poorly-controlled diseases such as rheumatoid arthritis and psoriasis, and cardiovascular disease.
Abstract 318: Circulating Neutrophils and their Secreted Mediator S100A8/A9 Correlate with Carotid Artery Disease and Predict Cardiovascular Events in Healthy Individuals
Authors: Cotoi Ovidiu S , Ko Nayoung , Dunér Pontus , Björkbacka Harry , Hedblad Bo , Nilsson Jan , Schiopu Alexandru 
Published: March 2022

Aims
S100A8/A9 is an inflammatory mediator secreted by activated neutrophils and monocytes/macrophages. Serum S100A8/A9 levels were previously found to correlate with the severity of coronary artery disease in diabetic patients and to predict cardiovascular (CV) events in healthy postmenopausal women. Our aim was to investigate whether S100A8/A9 correlates with carotid artery disease and whether it can predict CV risk in healthy individuals.

Methods
We measured baseline levels of S100A8/A9 in 664 individuals with no previous history of CV disease, randomly selected from the Malmö Diet and Cancer cohort. We examined the correlation between S100A8/A9 and traditional CV risk factors, circulating cell populations, plasma cytokines, carotid intima media thickness (IMT) and area (IM area), and the incidence of CV events during a follow-up period of 16.2 years.

Results

We detected significant positive correlations between baseline S100A8/A9 and the number of circulating neutrophils, IFNγ, TNFα, IL-1β, smoking, BMI, systolic blood pressure and an inverse correlation with HDL. In a multivariate linear regression model adjusted for age and sex, S100A8/A9 and the neutrophil counts were correlated with IMT and IM area in the common carotid artery. The associations with IM area remained significant after further adjustment for CV risk factors. In a Cox regression model corrected for age and sex, S100A8/A9 and circulating neutrophils predicted the incidence of coronary events (fatal or non-fatal myocardial infarction) [HR (95%CI) per SD: 1.28 (1.03-1.59),
P
=0.026 and 1.26 (1.04-1.53),
P
=0.020, respectively] and CV death [1.34 (1.06-1.71),
P
=0.015 and 1.59 (1.33-1.90),
P
<0.001, respectively]. There was no relationship with stroke.

Conclusions
S100A8/A9 correlates strongly with circulating neutrophil numbers, but not with monocytes or monocyte sub-populations. Baseline S100A8/A9 concentrations and circulating neutrophils are significantly associated with carotid artery disease and predict coronary events and CV death in apparently healthy individuals. Our study provides further evidence for the involvement of activated neutrophils in atherogenesis and acute coronary events.