bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3: Apolipoprotein A-I Inhibits Streptococcal Cell Wall-Induced Arthritis in the Rat in an ABCA1-dependent Manner
Authors: Wu Ben J , Ong Kwok L , Shrestha Sudichhya , Chen Kang , Barter Philip J , Rye Kerry-Anne 
Published: July 2021

Introduction.
Arthritis is a chronic inflammatory disease characterized by joint inflammation and destruction, reduced high-density lipoprotein (HDL) levels, and increased cardiovascular risk.

Objective
To determine if apolipoprotein (apo) A-I, the main HDL apolipoprotein, prevents joint inflammation in arthritis.

Methods and Results
In vivo: Arthritis was induced in female Lewis rats with a single 15 mg/kg intraperitoneal streptococcal cell wall peptidoglycan-polysaccharide (PG-PS) injection and quantified as a combined forepaw and hindpaw inflammation score. Arthritis progressed from an initial, acute phase of joint inflammation during the first 4 days post-PG-PS administration to remission by day 8, followed by chronic joint inflammation up to sacrifice at day 21. Two intravenous infusions of lipid-free apoA-I (8 mg/kg) 24 h pre- and 24 h post-PG-PS injection reduced the acute and chronic joint inflammation by 63±9% at day 3 and by 61±8% at day 21. Infusion of apoA-I at days 7, 9 and 11 post-PG-PS injection reduced the chronic response by 43±11% at day 21. ApoA-I infusions at 24 h prior to and at days 1, 7, 9, 11 post-PG-PS injection reduced joint inflammation by 61±5% at day 3 and by 90±5% at day 21 (p<0.05 for all vs saline infusion). These beneficial effects of apoA-I were accompanied by a reduced inflammatory white blood cell count, reduced pro-inflammatory cytokine levels in synovial fluid, and reduced macrophage accumulation, toll-like receptor 2 (TLR2) and inflammatory cytokine expression in synovial tissue. In vitro: Human monocyte-derived macrophages (HMDMs) were pre-incubated with lipid-free apoA-I, then stimulated with PG-PS (20 μg/mL). Pre-incubation with apoA-I inhibited PG-PS-induced TLR2 and MyD88, a TLR2 adapter protein, expression. Nuclear factor-κB activation and pro-inflammatory cytokine production were also attenuated. These anti-inflammatory effects of apoA-I were abolished in HMDMs transfected with ATP-binding cassette transporter 1 (ABCA1) siRNA.

Conclusions
These findings establish that apoA-I attenuates PG-PS induced arthritis in the rat. These effects may involve ABCA-1 and inhibition of TLR2 expression and activation.
Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction
Authors: Kujiraoka Takehiko , Satoh Yasushi , Ayaori Makoto , Shiraishi Yasunaga , Arai-Nakaya Yuko , Hakuno Daihiko , Yada Hirotaka , Endo Shogo , Isoda Kikuo , Adachi Takeshi 
Published: July 2021

Background
Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction.

Methods

Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca
2+
-ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta.

Results
The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them.

Conclusions

Hepatic ERK2 revealed the suppression of hepatic ER stress and HST
in vivo
, which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.
Abstract 483: Clot Degradation Assay for the Analysis of Vascular Bed Fibrinolytic Reactivity
Authors: Clark Amanda L , Kumar Neil , Roztocil Elisa , Gillespie David , Cullen John P 
Published: July 2021

Introduction

Pulmonary emboli cause significant morbidities and risk of mortality to affected patients, yet the mechanism behind their formation is still elusive. A greater understanding of clot formation and fibrinolysis in the pulmonary artery (PA) and iliac vein (IV) vascular beds has become an important area of research in order to find better therapeutics for the treatment of deep vein thrombi and pulmonary emboli. The aim of this study was to develop a novel
in vitro
clot degradation assay for the comparison of fibrinolytic reactivity of different vascular beds.

Methods

Thrombin was added to fibrinogen at 37
°
C for 24 hours and the resulting fibrin clot was centrifuged, dried and weighed. Human PA and IV endothelial cells were incubated for 24 hours and cellular extract and media samples were collected and evaluated for their ability to degrade fibrin clots in the presence of plasminogen. Fibrinolysis, stimulated by plasmin formed by endothelial cell derived plasminogen activator, was measured as percent clot degradation by weight.

Results

Fibrinogen and thrombin dose responses were completed to find the appropriate concentrations of each to use for clot formation: fibrinogen (6.04x10
-6
M) and thrombin (0.0005 NIH units). To validate the clot degradation assay, a uPA dose response was conducted from 150fM to 15nM uPA and demonstrated that each ten-fold increase in uPA concentration corresponded to an average of 14% degradation (p<0.05, n=3) up to 72.5% degradation in the presence of 15 nM uPA. While PA cell extracts showed no effect on clot degradation, IV cell extracts increased degradation by 30%. However, when clots were exposed to PA media there was a 14% increase in clot degradation (p<0.05, n=3), whereas the corresponding IV media samples had no effect on clot weight.

Conclusions
This study demonstrates the development of a novel and reproducible methodology to examine fibrinolytic reactivity in cell culture samples. Endothelial cells from the pulmonary artery circulation exhibit greater ability to extrinsically degrade fibrin clots when compared to endothelial cells from the iliac venous bed which may explain, in part, why more clots are found in the deep veins and not the pulmonary vasculature.
Abstract 530: Diurnal and Day-to-Day Variability of Endothelial Progenitor Cells
Authors: Campia Umberto , Saber Rana , Liao Yihua , Liu Kiang , MDermott Mary , Vaughan Douglas , Lloyd-Jones Donald 
Published: July 2021

Background
Circulating endothelial progenitor cells (EPCs) may contribute to vascular repair. Whether a diurnal and/or day-to-day variability of circulating EPCs is physiologically present in healthy adults has not been investigated.

Methods
Eighteen healthy adults underwent EPCs count on three different time points: two in the same day between 7:00 and 8:30 and between 12:30 and 14:00; and one in another day between 7:00 and 8:30. EPCs (CD34+CD45lo; CD34+CD45loCD133+; and CD34+CD45loCD31+) were quantified using multi-parameter flow cytometry and an ISHAGE based gating strategy. Variability of EPCs was assessed by coefficient of variation (CV) between time points in the same day and in different days.

Results
Baseline participant characteristics are reported in table 1. EPCs measurements and CVs are reported in table 2.

Conclusions
In healthy middle-aged adults, circulating EPCs appear to have a marked diurnal variability but a low day-to-day variability. Further study is needed to understand the mechanisms of EPCs variability and its biological significance.
Abstract 69: Anacetrapib Dose-dependently Decreases Atherosclerosis Development and Adds to the Beneficial Effects of Atorvastatin in APOE*3Leiden.CETP Mice
Authors: Kühnast Susan , van der Tuin Sam J , Havekes Louis M , Willems van Dijk Ko , Rensen Patrick C , van der Hoorn José W , Jukema J W , Princen Hans M 
Published: July 2021

Introduction
The residual risk of cardiovascular disease that remains after statin treatment has triggered the search for a secondary treatment target. Epidemiological studies propose HDL-cholesterol (HDL-C) as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. In human intervention trials, the CETP inhibitor anacetrapib decreases (V)LDL-C by 30-40% and increases HDL-C by 40-140%.

Hypothesis
Complete inhibition of CETP activity may result in adverse effects as compared to partial inhibition due to the appearance of a dysfunctional HDL. We, therefore, evaluated the effect of a broad treatment window of anacetrapib-induced CETP inhibition with partial to full inhibition, as well as the combination of atorvastatin and anacetrapib on atherosclerosis development in APOE*3Leiden.CETP mice.

Methods
Female mice were fed a Western-type diet containing 0.1% cholesterol without or with incremental dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/d), atorvastatin (2.4 mg/kg/d) or a combination of anacetrapib (0.3 mg/kg/d) and atorvastatin (2.4 mg/kg/d) for 20 weeks. Effects on plasma lipids, CETP activity and levels, as well as atherosclerotic lesion size and severity were assessed.

Results
Anacetrapib dose-dependently reduced CETP activity (-60% to -100%, P<0.001) and increased CETP levels (+13% to +31%, P<0.05), thereby decreasing nonHDL-C (-23% to -44%, P<0.001) and increasing HDL-C (+32% to +88%, P<0.001). Atorvastatin decreased CETP activity (-29%, P<0.001) and nonHDL-C (-36%, P<0.001). Anacetrapib dose-dependently decreased atherosclerotic lesion size (-36%, P<0.05 to -92%, P<0.001) and the percentage severe lesions. Anacetrapib added to the effects of atorvastatin by further reducing nonHDL-C (-36%, P<0.001), increasing HDL-C (+72%, P<0.001) and decreasing lesion size (-86%, P<0.001) and severity. Results on lesion composition are pending.

Conclusions
Anacetrapib dose-dependently decreases atherosclerosis development and adds to the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. Total blockage of CETP activity does not reveal adverse effects as compared to partial blockage.
Abstract 149: Regulator of G-Protein Signaling-1 Modulates Leukocyte Trafficking in Atherosclerosis and Aortic Aneurysm Formation Through Chemokine Receptor Desensitization
Authors: Patel Jyoti , McNeill Eileen , Douglas Gillian , Hale Ashley , de Bono Joseph , Greaves David R , Channon Keith M 
Published: July 2021

The regulation of macrophage recruitment and retention into the vascular wall is critical in the progression of atherosclerosis and aortic aneurysm formation. This can be mediated by chemokine activation of multiple G-protein coupled receptors. The Regulator of G-Protein Signaling-1 (RGS1) acts to deactivate the intracellular response to sustained chemokine stimulation. We have found that RGS1 is upregulated with atherosclerotic plaque progression and with monocyte-macrophage activation but its role is unknown.
Rgs1-/- macrophages have significantly enhanced migratory responses to atherogenic chemokines and have impaired desensitization to chemokine re-stimulation (p<0.001). In vivo, RGS1 has a role in the accumulation of macrophages in atherosclerotic lesions and during Angiotensin II (AngII) aortic aneurysm rupture. In the absence of RGS1, atherosclerosis and macrophage accumulation is attenuated in early lesions in the aortic root and aortas of ApoE-/- mice (p<0.001). Rgs1-/- mice are protected from AngII induced aneurysm rupture compared to ApoE-/- mice with 94% survival vs. 56%. Rgs1-/- mice have significantly fewer CD11b+ myeloid cells and CD14+ macrophages in aortas than ApoE-/- mice (p<0.05) after 5 days of AngII infusion.
Following bone marrow transplantation, recipient mice receiving ApoE-/- bone marrow were more susceptible to aortic aneurysm rupture (p=0.0124), indicating bone marrow-derived RGS1 is required for aneurysm rupture. Furthermore, AngII treatment increased systolic blood pressure to a greater extent in Rgs1-/- mice than ApoE-/- mice suggesting aneurysm formation in these mice is independent of AngII induced hypertension and this is mediated by vascular-derived RGS1. To gain insight into the mechanism by which RGS1 regulates trafficking, we selectively labelled inflammatory monocytes in vivo to track their movement into aortas following AngII infusion. We found an accumulation of labelled CD45+ cells in the aortas of ApoE-/- mice from day 3 to day 5 but not in Rgs1-/- mice indicating RGS1 as a regulator of macrophage retention in aortic aneurysms.
These findings identify a novel role for RGS1 in leukocyte retention in vascular inflammation, highlighting RGS1 as a potential target in cardiovascular disease.
Abstract 213: Phospholipid Transfer Protein Deficiency Attenuates High-Fat Diet--Induced Obesity and Insulin Resistance
Authors: Song Guohua , Zong Chuanlong , Shao Mingzhu , Yu Yang , Guo Shoudong , Liu Qian , Zhao Hui , Lin Quanqiang , Wang Xinnong , Lee Phoebe , Luo Yi , Jiang Xian-Cheng , Qin Shucun 
Published: July 2021

Increased phospholipid transfer protein (PLTP) activity has been found to be associated with diabetes, obesity, and metabolic syndrome in humans. However, whether or not PLTP has a direct effect on insulin sensitivity and obesity is largely unknown. Here we analyzed the effect by using PLTP knockout (PLTP-/-) mouse model. Although, PLTP-/- mice have normal body-weight-gain under chow diet, these mice were protected from high-fat-diet-induced obesity and insulin resistance, compared with wild type mice. In order to understand the mechanism, we evaluated insulin receptor and Akt activation and found that PLTP deficiency significantly enhanced phosphorylated insulin receptor and Akt levels in high-fat-diet fed mouse livers, adipose tissues, and muscles after insulin stimulation, while total Akt and insulin receptor levels were unchanged. Moreover we found that the deficiency induced significantly more GLUT4 immunostaining in the plasma membranes of adipocytes and muscle cells after insulin stimulation. Finally, we found that PLTP deficient hepatocytes had less sphingomyelin and free cholesterol in the plasma membrane and lipid raft than that of controls and this may provide a molecular basis for PLTP deficiency-mediated increasing in insulin sensitivity. We have concluded that PLTP deficiency leads to an improvement in tissue and whole-body insulin sensitivity in high-fat-diet induced insulin resistance mice model.
Foundation:National Natural Science Foundation of China (# 81070247, 81170785) and Taishan Scholar Foundation of Shandong Province.
Abstract 567: A Successful Use of Tissue Plasminogen Activator and Argatroban for Acute Therapy of a Submassive Pulmonary Embolism Caused by Heparin-Induced Thrombocytopenia
Authors: Assaad Murad , Ataya Samy , Ha Linda 
Published: July 2021

The field of anticoagulation has become a highly relevant and expanding division of medicine. Clinicians must maintain an adequate knowledge of the indications, risks, and benefits of each particular anticoagulant before utilizing them in patient care. Despite great advancements in anticoagulate therapies, areas of uncertainty exist when applying combined use of anticoagulants. This vignette illustrates a unique circumstance of initial therapy combining argatroban with tissue plasminogen activator (tPA) and subsequent transition to warfarin in the management of submassive pulmonary embolism (PE) caused by heparin-induced thrombocytopenia (HIT). There are currently no other published cases or guidelines that have demonstrated this treatment strategy.
We present the case of a 56-year-old African American female who was started on argatroban therapy for submassive bilateral PE secondary to HIT. She required tPA after becoming progressively unstable. The argatroban drip was continued without any hemorrhagic complications. This combination of therapy led to her stabilization, and she was ultimately safely transitioned to warfarin therapy for long term maintenance anticoagulation.
Argatroban is effective in the prevention and treatment of life-threatening complications of HIT. Very little research has been conducted in patients receiving tPA followed by anticoagulation therapy. This case highlights the successful therapy with combined use of tPA and argatroban followed by warfarin transition in the treatment of submassive PE caused by HIT. We find that tPA was safe and effective when the initial argatroban failed to stabilize our patient. The continued use of argatroban infusion after tPA did not cause any hemorrhagic complications. Furthermore, the overlap use of warfarin with argatroban until an INR greater than 4 was achieved for maintenance therapy did not contribute to any hemorrhagic complications. We conclude that the combination of tPA and argatroban is effective in the acute management of hemodynamically unstable PE caused by HIT without significant hemorrhagic complications.
Abstract 600: Novel Assays to Determine in vivo Platelet Activation
Authors: Sosa Iberia R , Zagol-Ikapitte Irene , Bala Manju , Boutaud Olivier , Oates John 
Published: July 2021

In vivo platelet activation is associated with several pathologic entities, including acute coronary syndrome, essential thrombocythemia, anti-phospholipid antibody syndrome, diabetes and metabolic syndrome. The need for more robust biomarkers with which to assess platelet activation in vivo in human diseases is well recognized. Our lab has developed two novel assays to study in vivo platelet activation and rate of turnover.
During platelet activation, malondialdehyde (MDA) is produced by the thromboxane synthase in amounts equimolar to thromboxane A2 and also non-enzymatically by lipid peroxidation resulting from the oxidative processes that accompany activation. MDA is a reactive dicarbonyl that reacts with amines, notably lysines on proteins, yielding covalent modifications of the proteins that then accumulate over the lifetime of the platelet. We developed an LC/MS/MS method for quantification of the most stable of three MDA adducts, the dilysyl-MDA crosslink, employing a [13C12] labeled internal standard. We found that activation of platelets with arachidonic acid leads to an increase in the levels of dilysyl-MDA crosslinks in platelets, which is inhibited by the thromboxane synthase inhibitor, ozagrel, by the cyclooxygenase inhibitor, aspirin, and by scavengers of reactive carbonyls, 3- methoxysalicylamine and Salicylamine.
High platelet turnover has been associated with increased risk for thrombosis and failure of antiplatelet agents. We propose a novel approach to studying platelet turnover by labeling platelets in vivo by oral administration of aspirin containing a deuterium labeled acetyl group (d3-aspirin). We can measure the clearance of d3-labeled platelets by using LC/MS/MS to measure the tryptic peptide (SLK) of COX-1 labeled with d3. This approach avoids exposure to radioactivity and the artifact resulting from manipulation of platelets labeled ex vivo.
The results of this study provide two novel assays with the potential to serve as markers of in vivo platelet activation and turnover, which may be useful in predicting thrombotic risk and efficacy of antiplatelet therapy in patients with medical conditions associated with platelet hyperactivity and high rate of platelet turnover.
Abstract 676: Microrna-30 and Cthrc1: Translating Aging into Vascular Stiffness and Abdominal Aortic Aneurysm
Authors: Spin Joshua M , Zheng Wei H , Adam Matti , Raaz Uwe , Schellinger Isabel , Kayama Yoseke , Toyama Kensuke , Deng Alicia , Maegdefessel Lars , Tsao Philip S 
Published: July 2021

Abdominal aortic aneurysm (AAA) is a major source of vascular morbidity and mortality, with increasing age representing one of the strongest risk factors. While increases in aortic extra-cellular matrix deposition may be protective, changes in vessel architecture with age result in heterogeneous stiffness and vascular calcification, which appear to pre-dispose to AAA development. MicroRNAs (miRs) are key regulators of vascular homeostasis and pathobiology.
Array profiling and qRT-PCR of aneurysmal aortic tissue in a murine AAA model (elastase-infused C57/B6) showed significant down-regulation of the miR-30 family, which is believed to have a role in vascular calcification. Increased age augmented this response, particularly for miR-30a, 30b and 30c. RNASeq profiling of a related AAA model (Ang-II in ApoE-/- KO) showed similar aortic down-regulation. Further, of differentially down-regulated miRs, miR-30 had the highest inverse correlation with mRNA gene targets. One predicted target - Cthrc1 (collagen triple helix repeat containing-1) - was the most consistently and significantly up-regulated gene across all time points in the AAA models. The protein resides within vascular smooth muscle cells (SMCs) and fibroblasts, responds to injury, and may regulate collagen expression and deposition. Immunofluorescence staining of AAA vs. normal aortas revealed increased expression of CTHRC1.
We further found that miR-30 family members bind to the CTHRC1 3’ UTR and regulate gene expression in vitro, and that antagomir suppression of miR-30 upregulates CTHRC1 in SMCs. We also demonstrated that signaling pathways known to increase in activity with aging within the aorta, and which are associated with vascular calcification and fibrosis (e.g. IL6-based inflammatory signaling, TGF-β signaling, and BMP-2 signaling) down-regulate miR-30 family expression in SMCs, and inversely up-regulate CTHRC1 expression. Forced overexpression of miR-30 in SMC in vitro down-regulates RUNX2, a key promoter of vascular stiffness and calcification. Taken together, these results suggest a significant role for miR-30 in pathways related to matrix deposition and calcification, regulating aortic pathobiology and age-related susceptibility to AAA.