tbuckley/cabot-search huggingface dataset:
Abstract 5157: Atherosclerotic Plaque Development Depends on T-cell Priming Within the Secondary Lymphatic Organs
Authors: Maren M Luchtefeld, Christina Grothusen, Oliver Pabst, Reinhold Förster, Schieffer Bernhard
Journal: Circulation (2009)

Background : The chemokine receptor 7 (CCR7) is required for the migration of dendritic cells and T-cells to the secondary lymphoid organs (SLO) in order to promote DC-dependent T-cell priming. Here we investigated the influence of CCR7-deficiency on T-cell distribution in animals on cholesterol rich diet. In vitro , we analyzed whether oxLDL induced the expansion of a T-cell carrying a specific T-cell receptor subset and whether this T-cell receptor could be found in animals fed with a high cholesterol diet. Finally we investigated whether atherosclerosis can be reconstituted when ex vivo primed T-cells were given to CCR7-deficient mice while feeding with a cholesterol rich diet. Methods and Results: T-cell number within the aorta was significantly increased, whereas T-cells within the SLO were reduced in ccr7 −/− /ldlr −/− mice compared to ldlr −/− -mice as analyzed by CD3 staining of serial sections (immunhistochemistry, n=12–17). OxLDL (10 μ g/mL) but not nLDL (10 μ g/mL) promoted DC maturation in vitro (CCR7 and MHC-II expression, n=4) and in vivo (CD80 and CD86 expression, n=4) as monitored by FACS-analysis. To characterize an oxLDL specific T-cell, we co-cultivated nLDL and oxLDL stimulated DCs with T-cells and analyzed T-cell activation (BrdU, n=5), and the expression of an oxLDL specific T-cell receptor subset (real-time PCR, n=4). OxLDL but not nLDL stimulated DCs induced T-cell proliferation, which was accompanied with the expression of the T-cell receptor chains V α 10 and V β 6. These T-cells could also be found within the aorta and the SLO of ldlr −/− -mice following feeding and was found to be significantly reduced in ccr7 −/− /ldlr −/− mice as analyzed by T-cell receptor expression (real-time PCR and FACS-analysis, n=4–5). Finally, to investigate whether this specific T-cell is responsible for atherosclerotic plaque development, we injected oxLDL expanded T-ells into ccr7 −/− /ldlr −/− mice while feeding with a cholesterol rich diet (1×10 7 cells) and observed a complete reconstitution of the atherosclerotic phenotype ( en face preparation of oil red stained aortas, n=5–14), Conclusion: Our results indicate that atherosclerotic plaque development is driven by an antigenic process induced by oxLDL and promoted by a specific T-cell.
Abstract 4913: Glutathione Peroxidase-1 Modulates the Effects of Tumor Necrosis Factor-alpha in Endothelial Cells by Regulating Dual Specificity Phosphatase 4
Authors: Edith Lubos, Neil J Kelly, Jane A Leopold, Ying-Yi Zhang, Joseph Loscalzo, Diane E Handy
Journal: Circulation (2009)

Reactive oxygen species (ROS) have been implicated in pro-inflammatory signal transduction activated by tumor necrosis factor- α (TNF- α ). For this reason, we examined the effect of glutathione peroxidase-1 (GPx-1), an important antioxidant enzyme, on TNF- α -induced changes in gene expression in endothelial cells. In human microvascular endothelial cells (HMVEC), we showed that suppression of GPx-1 mRNA by 96.6% (p&lt;0.0001) with siRNA (siGPx-1) increases ICAM-1 mRNA (3.6-fold, p&lt;0.01) and protein (7.1-fold, p = 0.0002) expression compared to siControl cells, and GPx-1 deficiency augments TNF- α -induced ICAM-1 mRNA (2.1-fold, p&lt;0.0001) and protein (2.5-fold, p = 0.001) expression, in part, by enhancing ROS production and prolonging I κ B α degradation and phospho-ERK1/2 activation. The antioxidants, N -acetyl-L-cysteine and diphenyleneiodonium chloride, or adenoviral over-expression of GPx-1 significantly attenuated these TNF- α -mediated responses. Similarly, endothelial cells cultured from GPx-1 knockout mice had augmented TNF- α -mediated ICAM-1 expression, whereas cells from transgenic mice overexpressing GPx-1 showed blunted responses to TNF- α , confirming that GPx-1 modulates the inflammatory response to TNF- α . To analyze further signaling pathways, we performed microarray analysis of HMVEC treated with TNF- α in the presence and absence of GPx-1. Among the genes whose expression changed significantly, dual specificity phosphatase 4 (DUSP4), an antagonist of MAPK signaling, was downregulated 3.2-fold (p&lt;0.005) by GPx-1 suppression. Quantitative real time PCR confirmed that GPx-1 deficiency enhanced DUSP4 suppression by TNF- α (p&lt;0.01). Targeted knockdown of DUSP4 mRNA by 78.5% (p&lt;0.0001) significantly increased TNF- α -mediated ICAM-1 and VCAM-1 gene expression (p&lt;0.01 and p&lt;0.012, respectively), suggesting that loss of DUSP4 is sufficient to augment TNF- α -mediated induction of adhesion molecule expression. Taken together, these data show that GPx-1 modulates endothelial cell activation by TNF- α , in part, by modulating DUSP4 expression. These results highlight a novel mechanism by which GPx-1 modulates ROS-dependent signaling in endothelial cells.
Abstract 5168: Adenosine Formed by CD73 on Treg Inhibits T-cell Mediated Immune Response via NFkB
Authors: Michael Romio, Benjamin Reinbeck, Sandra Burghoff, Jürgen Schrader
Journal: Circulation (2009)

CD73-derived adenosine (ADO) acts as potent inhibitor of inflammation and we have recently shown that the CD73−/−/ApoE−/− double mutants show enhanced plaque formation with local accumulation of immune cells. Since regulatory T-cells (Treg) have been recently shown to express CD73 as a novel marker enzyme, the present study explored the potential role of CD73-derived adenosine on NFkB activity and cytokine release in CD4+ cells. We asked: does adenosine physiologically formed by Treg inhibit the immune response of the entire Th-cell population? Does the lack of CD73 alter the expression pattern of various enzymes of the ecto-nucleotidase cascade and ATP/adenosine receptors in Tregs? T-cells, isolated from murine spleens by magnetic micro beads, were stimulated with α CD3/ α CD28 which activates the nuclear translocation of transcriptionfactor NF κ B, known to be involved in the secretion of pro-inflammatory cytokines such as IL-2. Using EMSA we found activated NF κ B in T-cells lacking CD73 to be significantly upregulated (WT: 4.36±0.21, CD73−/−: 6.58±0.75; n=4; p=0.029) which was paralleled by increases in release of the pro-inflammatory cytokines IL-2 and IFN- γ (ELISA). Treatment of T-cells with ADO (25 μ M) caused a massive A2a ADO receptor mediated reduction of IL-2 and IFN-ã release. Similarly, AMP (50 μ M) decreased the IFN-ã release of WT CD4+ cells. Expression analysis revealed that there were no differences in the enzymes and receptors of the ecto-nucleotidase cascade in WT and CD73−/− Tregs. Upon stimulation with ãCD3/ãCD28, however, mRNA levels of the ATP receptor P2X7 - a ligand-gated ion channel that controls CD4+ activation - was significantly reduced. Expression of the ADO transporter CNT2 was also significantly reduced while the expression of the A2b ADO receptor was increased. In summary, our data show that stimulated CD73-deficient T-cells show a proinflammtory phenotype with increased levels of active NF κ B and released proinflammatory cytokines. Thus, CD73-derived ADO is a physiological inhibitor of the immune response relevant to atherogenesis. Downregulation of P2X7 on Tregs may be important to prevent apoptosis and to maintain suppressive function of Tregs by converting extracellular ATP to ADO.
Chromosome 9p21 Variant Predicts Mortality After CABG Surgery
Authors: Jochen D Muehlschlegel
Journal: Circulation (2009)

Abstract #4222 Jochen D Muehlschlegel, Kuang-Yu Liu, Tjörvi E Perry, Amanda A Fox, Harvard Medical Sch, Boston, MA; Charles D Collard, Baylor Coll of Med, Houston, TX; Stanton K Shernan, Simon C Body, Harvard Medical Sch, Boston, MA; CABG Genomics Investigators Jochen D Muehlschlegel, 2009 Finalist and Presenting Author
Abstract 4198: Short-term Clinical Consequences of Nonadherence in Patients with Hypertension and Multiple Risk Factors
Authors: Spencer B Cherry, Mohammed A Hussein, Michael B Nichol, Simon S Tang, Joshua S Benner
Journal: Circulation (2006)

Objective: To quantify the short-term clinical consequences of nonadherence to concomitant antihypertensive (AH) and lipid-lowering (LL) therapy among primary prevention patients with hypertension and multiple risk factors. Design and Methods: A microsimulation model was developed to compare cardiovascular event rates over 3 years under 3 treatment scenarios: no treatment, typical adherence, and ideal adherence. Population characteristics were modeled on the ASCOT-LLA study. The “no treatment” scenario represented a natural-history model, with CHD (non-fatal MI, angina pectoris, or CHD death) and stroke probabilities determined by Framingham Heart Study risk equations. “Ideal adherence” incorporated adherence levels and risk reduction from ASCOT-LLA. “Typical adherence” reflected time-dependent annual transitions among three adherence categories based on data from a U.S. Medicaid population: non-adherent (≤ 20% days covered), partially adherent (20 − 80%), or fully adherent (≥ 80%). This scenario assumed a linear association between adherence and risk reduction. Results: In the “no treatment” scenario, event rates per 1,000 patient-years were 15.1 and 8.1 for CHD and stroke, respectively. The typical adherence scenario yielded fewer CHD events (relative risk 0.68 [95% CI 0.63– 0.72]) and stroke events (0.68 [0.62– 0.74]). Full adherence to both treatments would yield greater reductions in CHD (0.40 [0.37– 0.43]) and stroke (0.51 [0.47– 0.57]). Increasing adherence from typical to ideal levels would prevent an incremental 1200 CHD events and 400 stroke events per 100,000 treated patients over a 3-year period. Conclusions: With typical AH and LL adherence, hypertensive primary prevention patients with multiple risk factors can be expected to receive approximately 57% of the potential protection from CHD and stroke events associated with full adherence.
Abstract 5018: Soluble fms-like Tyrosine Kinase (sFLT1): A Biomarker of Endothelial Origin in Acute ST-segment Elevation Myocardial Infarction (STEMI)
Authors: Navin K Kapur, Adil A Yunis, Tuan A Nguyen, Peter Parpos, Barath Krishnamurthy, Brian J Cross, Mark Aronovitz, Andrew Weintraub, Carey Kimmelstiel, Iris Z Jaffe, Richard H Karas, Michael E Mendelsohn
Journal: Circulation (2009)

In STEMI, early recognition improves clinical outcomes. Current biomarkers of myocardial necrosis are limited by poor sensitivity and specificity during the acute phase of coronary occlusion. sFLT1 is an endothelial-derived, hypoxia-inducible protein. We hypothesized that vascular occlusion induces early expression of sFLT1 in STEMI. Methods &amp; Results: In a prospective, observational study, serum sFLT1 levels were measured by ELISA in 30 patients with STEMI referred for emergent catheterization. Compared to 20 healthy, age-matched controls, sFLT1 levels were markedly increased at the time of presentation (11.7±2 vs 210.5±80 pg/mL, p&lt;0.0001), then substantially reduced within 24 hours of reperfusion (22.3±15 pg/mL, p&lt;0.0001). On admission, 100% of STEMI patients had elevated sFLT-1 levels (&gt;50pg/mL), whereas 73% and 64% had levels of CK-MB &gt;5ng/mL and Troponin-I &gt;1.0 ng/mL respectively. Two patients undergoing alcohol septal ablation were studied as positive controls. sFLT1 levels increased within 40 minutes of occlusion (27.8 vs 216.2 pg/mL, pre- vs post-ablation, p&lt;0.03). We also studied sFLT1 expression in a mouse model of myocardial infarction (MI). After 1 hour of left coronary ligation in 10-week old male wild-type mice (n=6/group), left ventricular sFLT1 mRNA levels were increased (p&lt;0.01 MI vs. sham), while aortic and lung mRNA expression were unchanged. Serum sFLT1 levels were also elevated in MI (170±71 vs 541±107pg/mL, sham vs. MI, p&lt;0.002). To explore the cellular origin of sFLT1, human coronary endothelial (HCE) and smooth muscle cells (HSMC) were rendered hypoxic. Within 1 hour, sFLT1 mRNA expression in HCE increased by 173±35% (p=0.03). By 12 hours, sFLT1 mRNA and protein expression in hypoxic HCE increased by 313±15% (p&lt;0.01) and 256±17% (p&lt;0.001) respectively. To simulate the effects of reperfusion on sFLT1 expression, HCE were exposed to 12 hours of hypoxia, then 6 hours of normoxia. After normoxic rescue, sFLT1 protein expression decreased by 36% (p&lt;0.01, vs hypoxic HCE). Hypoxia failed to induce sFLT1 mRNA or protein expression in HSMC. Conclusion: sFLT1 is a highly sensitive biomarker of vascular occlusion released by the endothelium during the acute phase of STEMI and may be an important new marker for acute ischemic syndromes. This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
Abstract 5006: Aspirin Non-Response as Determined by Multiple Platelet Function Assays
Authors: Meadhbh McCall, Aaron Peace, Tony Tedesco, Ronan Conroy, David Foley, Dermot Cox
Journal: Circulation (2009)

Background. While low dose aspirin has become the standard of care for the prevention of cardiovascular events there is evidence that enteric aspirin may not be as effective as plain aspirin. Methods. We screened 138 patients with cardiovascular disease who were taking aspirin and measured their aspirin response with three platelet function assays: Light Transmission aggregometry (LTA) with arachidonic acid, the VerifyNow™-Aspirin and Thromboxane B 2 (TxB 2 ) ELISA. Resistance was defined as &gt;20% aggregation by LTA, &gt;550 ARU in the VerifyNow™ and &gt;10 ng/ml by TxB 2 ELISA. Patients aspirin preparations were altered and dosages increased to a maximium of 300mg plain aspirin if patients showed lack of response to their aspirin by any one assay. Results. 24% of patients were non-responders in at least one assay. There was 13% agreement between LTA and TxB 2 , 9% between TxB 2 and VerifyNow™ and 19% between VerifyNow™ and LTA. Only 9% of patients defined as resistant by one assay were resistant to all three. Upon repeat measurement, with compliance encouraged (through education) and assured (directly observed) only 6.5% of patients were still non-responders in at least one assay. Compliant non-responding patients were heavier than the responding population (98.5kg versus 77.9kg). Only 2.7% (105kg) of the cohort remained non-responders after swtiching their aspirin preparations from enteric-coated to plain. Increasing aspirin dosage to 150mg plain aspirin resulted in 0.4% non-response. Conclusions. These data show that whilst aspirin non-response is a problem, there is significant inter-assay agreement making it difficult to define. However, over 2/3 (69.6%) of non-responding patients became responders after encouraging compliance. The remaining patients were heavier patients and switching to plain aspirin which has a higher bioavailability improved their response to aspirin. Only 1 patient could be detected who did not respond to aspirin suggesting that aspirin resistance is very rare and most cases are due to poor compliance or underdosing in heavier patients exacerbated by the lower bioavailability of enteric-coated aspirin. While there was poor agreement between assays they were effective at identifying non-compliant patients.
Abstract 5220: Cannabinoid Receptor Activation Protects Coronary Endothelium Against Reperfusion Induced Intercellular Gap Formation in a Cellular Model of Ischemia and Reperfusion
Authors: Sascha A Kasseckert, Mustafa Micoogullari, Hans M Piper, Klaus-Dieter Schlüter, Yaser Abdallah
Journal: Circulation (2009)

Ischemia and reperfusion provokes barrier failure of the coronary microvasculature through activation of the endothelial contractile machinery and formation of intercellular gaps, leading to myocardial edema development that jeopardizes functional recovery of the heart. In vivo studies have shown that cannabinoid receptor (CBR) activation protects reperfused hearts against reperfusion injury in terms of infarct size reduction and functional recovery. The aim of the present study is to investigate whether CBR activation with the CBR agonist R1-Methanandamide (R1M, 10 μ M) can protect coronary endothelium against reperfusion induced intercellular gap formation. Cultured rat coronary endothelial monolayers were subjected to conditions of simulated ischemia (ANoxia 40min; pH6.4; no glucose) and reperfusion (NORMoxia 40min; pH7.4; with glucose). Stimulation of cannabinoid receptors during reperfusion significantly reduced reperfusion-induced intercellular gap formation (gaps[a.U.]:control:283±21; R1M:172±10*; n=12–16; *p&lt;0.05 vs. control). CB1 receptor blocking with AM251 [250nM] during reperfusion and R1M application completely abolished the R1M mediated protection (gaps[a.U.]: R1M+AM251: 269±32#; n=10; #p&lt;0.05 vs. R1M). Whereas the protective effect of R1M application during reperfusion could be further enhanced if AM630 [300nM], a CB2 receptor antagonist, was added to the reperfusion medium simultaneously to R1M application (gaps[a.U.]: R1M+AM630:132±23#; n=12; #p&lt;0.05 vs. R1M). Inhibition of nitric oxide synthases (NOS) through application of L-NAME [200 μ M] during reperfusion significantly blunts the protection against reperfusion induced gap formation (gaps[a.U.]:control:305±29; R1M:221±21*; R1M+L-NAME:270±27#; n=6 – 8; *p&lt;0.05 vs. control; #p&lt;0.05 vs. R1M). In conclusion, activation of endothelial cannabinoid receptors protects the coronary endothelium against reperfusion-induced gap formation. This protection is mediated through CB1 receptor mediated NOS activation, whereas simultaneous CB2 receptor activation diminishes this protective effect.
Abstract 5194: Pioglitazone Attenuates Angiotensin II-induced Atherosclerosis via a Smooth Muscle Cell-Specific PPARgamma Mechanism but Has No Effect on Abdominal Aortic Aneurysms
Authors: Venkateswaran Subramanian, Dennis Bruemmer, Jonathan Golledge, Alan Daugherty
Journal: Circulation (2009)

Objective: Chronic infusion of angiotensin II (AngII) augments development of atherosclerosis and induces abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Smooth muscle cells (SMCs) play a pivotal role in the development of these two pathologies. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have previously been shown to attenuate atherosclerosis in male mice. The purpose of the study was to determine the role of SMC-specific PPARgamma in ligand-mediated attenuation of AngII-induced atherosclerosis and AAAs. Methods and Results: Pairs of LDL receptor −/− mice with homozygous floxed PPARgamma alleles (PPARgammaf/f) were bred. Cre was expressed under the control of the SMC-specific promoter, SM22. Littermates were generated that did not express Cre (Cre0/0, n = 33) or were hemizygous for Cre (Cre1/0, n = 24). Male mice were fed a fat-enriched diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) with or without the PPARgamma agonist, pioglitazone (Pio - 20 mg/kg/day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1,000 ng/kg/min) by osmotic minipumps for 4 weeks. Pio administration attenuated AngII increased systolic blood pressure equivalently in both Cre0/0 and Cre1/0 groups. SMC-specific deficiency of PPARgamma or Pio administration had no effect on serum cholesterol concentrations and lipoprotein-cholesterol distributions. SMC-specific PPARgamma deficiency increased atherosclerosis (Cre1/0 = 11.6±1.5% versus Cre0/0 = 6.7±0.9% P&lt;0.05). Pio administration reduced atherosclerosis in Cre0/0 mice (Pio-Cre0/0 = 2.9±0.4% versus Control-Cre0/0 = 6.7±0.9%, P&lt;0.05, n=7–12 ), but failed to reduce atherosclerosis in mice with SMC-specific PPARgamma deficiency (Control-Cre1/0 = 11.6±1.5% versus Pio-Cre1/0 = 9.9±2.5%, P=NS). SMC-specific PPARgamma deficiency or Pio administration had no effect on AngII-induced AAAs as measured by ex vivo external diameter (Control-Cre0/0 = 2.0±0.2, Control-Cre1/0 = 2.4±0.4 versus Pio-Cre0/0 = 2.2±0.2, Pio-Cre1/0 = 1.9±0.2 mm, P=NS). Conclusion: Administration of Pio attenuates AngII-induced atherosclerosis via the activation of SMC-specific PPARgamma but did not influence formation of AAAs in male hypercholesterolemic mice. This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania &amp; West Virginia).
Abstract 5204: Vascular Remodelling in Patients With Psoriatic Arthritis: The Impact of Blood Pressure
Authors: Massimo Puato, Marco Zanardo, Carmen Tirrito, Giulia Balbi, Elisabetta Faggin, Marta Zanon, Roberta Ramonda, Valentina Modesti, Alessandro Lo Nigro, Andrea Doria, Paolo Pauletto
Journal: Circulation (2009)

Increased cardiovascular mortality have been observed in several immune mediated rheumatic diseases, including psoriatic arthritis (PsA). We evaluated subclinical atherosclerosis in PsA patients according with hypertensive status by studying non invasively structural and functional properties of arteries. We studied 41 consecutive patients with PsA (of whom, 48% hypertensives) attending hospital outpatient clinics. 40 normotensives healthy subjects (NC) and 18 hypertensives (HT-C) served as controls. We evaluated by B-mode ultrasound the carotid intima media thickness (IMT) expressed as mean-IMT (cumulative mean of mean IMT measured in each carotid segment, common, bulb, and internal carotid artery, bilaterally) and as M-MAX (cumulative mean of maximum IMT). Endothelial function was evaluated by post-occlusion flow mediated dilation (FMD) of the brachial artery using ultrasonography. NO-independent vasodilation was evaluated by the response to sublingual glyceril trinitrate (GTN). PsA had a higher mean-IMT compared to NC. Hypertensive PsA displayed higher M-MAX versus both HT-C (p=0.007) and normotensive PsA (p=0.026). FMD was lower in PsA than in NC, whereas there was no difference between hypertensive PsA, normotensive PsA, and HT-C. GTN response was similar in all groups. In conclusion, our data show that subclinical atherosclerosis is enhanced in PsA compared to NC. In PsA, the hypertensive status proved to exert an additional effect on M-MAX, a parameter of advanced pro-atherogenic remodeling. FMD was reduced in PsA irrespective of hypertensives status. Thus, PsA per se implies a pro-atherogenic remodeling which is enhanced by the hypertensive status.