tbuckley/cabot-search huggingface dataset:
Abstract 607: Degradation of Metabolic Post-translational Modification Sensitizes Cardiac Myocytes to Hypoxia
Authors: Gladys A Ngoh, Lewis J Watson, Linda T Harrison, Steven P Jones
Journal: Circulation (2006)

We have recently discovered an endogenous mechanism of cytoprotection in the heart that involves the post-translational modification of proteins with a metabolic signal. Although this stress-responsive modification (beta-O linkage of N-acetylglucosamine, i.e. O-GlcNAc) exerts profound salubrious effects on the myocardium in vivo, the details regarding the pathobiology of this modification in the cardiac myocyte remain unexplored. We hypothesized that O-GlcNAc levels decrease following hypoxia and that manipulation of these levels would affect cardiac myocyte survival. We subjected isolated cardiac myocyte cultures (n &gt;/= 4/ all groups) to hypoxia (3 hours) and reoxygenation (up to 1 hour). We measured O-GlcNAc levels and determined that they begin decreasing within 15 minutes, and continue to decrease through one hour, of reoxygenation in cardiac myocytes. Such a significant decrement (p &lt; 0.05 vs. baseline) in O-GlcNAc levels was associated with a reduction in mitochondrial membrane potential (according to TMRM via fluorescence microscopy) and release of LDH (via spectrophotometric assay) into the media. To further investigate the regulation of O-GlcNAc levels following hypoxia, we targeted the enzymes controlling the presence of O-GlcNAc on proteins. Blocking the addition of O-GlcNAc (with TT04) profoundly sensitized myocytes to cell death while blocking the removal of O-GlcNAc (with PUGNAc) preserved myocyte survival (according to TMRM microscopy and LDH assay). We conclude that augmentation of O-GlcNAc levels attenuates, while diminution of O-GlcNAc levels exacerbates post-hypoxic injury in cardiac myocytes.
Abstract 5165: Liver-x-receptor Activation Inhibits Chemokine Induced Cd4-positive Lymphocyte Migration
Authors: Daniel Walcher, Dusica Vasic, Philipp Heinz, Nikolaus Marx
Journal: Circulation (2009)

Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that activation of the nuclear transcription factor Liver-X-Receptor (LXR) limits plaque formation in animal models by modulating macrophage function. Previous data demonstrated LXR alpha and beta mRNA and protein expression in human CD4-positive lymphocytes. In addition, activation of LXR limits TH1-cytokine release from CD4-positive cells, but the role of LXR in lymphocyte migration remains currently unexplored. Therefore, the present study investigated whether LXR activation might modulate chemokine-induced migration of these cells. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.5±0.8 fold increase in cell migration (p&lt;0.05; n=12). Pretreatment of cells with the LXR activator T0901317 reduces this effect in a concentration-dependent manner to a maximal 0.9±0.4 fold induction at 1 μ mol/L T0901317 (p&lt;0.05 compared to SDF-1-treated cells, n=12). Similar results were received with the LXR activator GW3965. In addition, T0901317 also reduced RANTES-induced cell migration, suggesting an effect independent of the chemotactic stimulus employed. The effect of T0901317 on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, T0901317 inhibited the activation of the small GTPase Rac and the phosphorylation of the Myosin Light Chain (MLC). Pretreatment with the LXR activator also reduces f-actin formation as well as ICAM3 translocation to the uropod, both important steps in T cell migration. Transfection of CD4-positive lymphocytes with LXR α / β siRNA abolished T0901317 inhibitory effect on MLC-phosphorylation. LXR activation by T0901317 or GW3965 inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T-cell migration in early atherogenesis, LXR activators may be promising tools to modulate this effect.
Abstract 4912: Multidrug Resistance Associated Protein-1 (MRP-1) Regulates Endothelial Cell Apoptosis
Authors: Julian D Widder, Christian Kruempel, Daniela Fraccarollo, Georg Ertl, Johann Bauersachs
Journal: Circulation (2009)

The multidrug resistance associated protein-1 (MRP-1) is the main transporter of oxidized glutathione in endothelial cells, and blockade of MRP-1 prevents endothelial cell dysfunction induced by reactive oxygen species (ROS). We therefore sought to investigate the effect of MRP-1 downregulation on TNF α -induced endothelial cell apoptosis. HAEC’s were either transfected with a siRNA against MRP-1 or a negative control siRNA and treated with TNF α /cycloheximide(CHX ) for 3h or 6h. TNF α /CHX lead to endothelial cell apoptosis as indicated by Annexin V staining (FACS analysis) and increased cleavage of caspase 3 (Western blot). Downregulation of MRP-1 via siRNA significantly diminished Annexin V staining and caspase 3 cleavage. TNF α /CHX augmented endothelial cell superoxide production which was significantly attenuated by siRNA against MRP-1. Further, pre-treatment with the glutathione precursor N-acetylcysteine prevented cleavage of caspase 3. TNF α /CHX mediated activation of caspases 7 and 8 were reduced when MRP-1 was downregulated, while no influence was found on phosphorylation levels of the Fas-Associated protein with Death Domain (FADD). TNF α /CHX induced phosphorylation of p38-, ERK- and JNK-MAP-kinases. While phosphorylation of p38 MAP kinase and ERK was not influenced by MRP-1 downregulation, TNF α /CHX induced JNK phosphorylation was significantly attenuated in HAEC’s transfected with MRP-1 siRNA. These data indicate a major role for MRP-1 in regulation of TNF α /CHX-induced endothelial cell apoptosis via modulation of ROS levels, caspase activation, and JNK phosphorylation.
2006 Katharine A. Lembright Award—“The Thin Stream of Fear Trickling Through the Mind”: Impact of Anxiety in Cardiac Patients
Authors: Debra K. Moser
Journal: Circulation (2006)

Anxiety has both functionally appropriate and pathological consequences. Among people with cardiac disease, anxiety can be functionally appropriate when it triggers an individual to quickly seek treatment for acute cardiac symptoms. Anxiety, however, may have pathological consequences when it is persistent or severe. These consequences may include the following: difficulty adhering to prescribed treatments and making recommended lifestyle changes; adoption of or failure to change risky behaviors; increased risk for acute cardiac events; and increased risk for in-hospital complications after admission for acute coronary syndrome. Nevertheless, because anxiety is a universal emotion that is managed without consequence by many people, its significance is often ignored by healthcare providers. The purpose of this presentation is to describe findings from a biobehavioral program of research in which the impact of psychosocial (with a major emphasis on anxiety) and behavioral variables on biological outcomes has been systematically examined. In this program of research we have (1) examined and compared the intensity of anxiety in international samples of various cardiac patient groups; (2) determined gender differences in the expression of anxiety; (3) investigated factors predicting anxiety levels, including perceived control; (4) studied healthcare providers’ knowledge of anxiety assessment and their practices with regard to the assessment and management of anxiety; (5) determined the impact of anxiety on clinical outcomes in cardiac patients and elucidated mechanisms for the linkage; and (6) tested interventions to decrease anxiety and improve morbidity and mortality. We hope to improve patient outcomes on a widespread basis by placing anxiety in the forefront of clinical cardiac practice.
Abstract 4163: Higher Dose Exposure of Lovastatin is Not Associated with Adverse Hepatic Outcomes in Patients with Existing Liver Disease
Authors: Andrew L Avins, M Michelle Manos, Lynn Ackerson, TR Levin, Wei Zhao, Rosemary Murphy, Douglas J Watson, Peggy M Hwang, Amy R Replogle, Jeffrey G Levine
Journal: Circulation (2006)

OBJECTIVE: We have previously shown that the rate of subjects developing adverse liver outcomes was substantially lower during lovastatin-exposed periods compared to non-exposed periods in patients with pre-existing liver disease. The objective of this analysis was to estimate the dose-response relationship between differing levels of lovastatin exposure and adverse hepatic outcomes. METHODS: This was a retrospective cohort study. Eligible subjects were adult members of Northern California Kaiser Permanente with at least 2-fold ALT or AST elevations 6–18 months apart, evidence of chronic hepatitis B or C infection, or a diagnosis of a chronic liver disease. Outcomes included the composite of events as well as individual components: liver injury, defined as moderate (3X ULN&lt;ALT&lt;10X ULN) or severe (ALT&lt;10X ULN); development of clinical cirrhosis; liver failure. The dose-response relationships were analyzed by estimating the risk of each outcome in subgroups defined by quartiles of total cumulative lovastatin exposure. Each of these risks was compared to that in the lovastatin-unexposed reference group and a test for trend applied, using orthogonal polynomial contrasts on the coefficients of categorical levels of the exposure variable. RESULTS: 93,106 eligible patients were identified, of whom 15% had been exposed to lovastatin. A strong and monotonic dose-response relationship was found for the composite outcome and moderate liver-injury endpoints. For the composite endpoint, hazard ratios declined from 0.81 in the quartile with least lovastatin exposure to 0.44 in the highest exposed group ( p&lt; .00001). Similarly, for the moderate liver-injury endpoint, hazard ratios declined from 0.97 to 0.27 with increasing lovastatin exposure ( p&lt; .00001). CONCLUSIONS: Among patients with liver disease, lovastatin exposure was associated with a dose-dependent reduction in the risk of several liver-disease outcomes. These results do not support labeling recommendations for avoiding the use of lovastatin at higher doses in patients with liver disease nor the need to closely monitor LFTs during lovastatin treatment.
Abstract 5252: Long-Term Administration of Thiazolidinedione Improves Vasomotion of Coronary Arteries Irrespective of Improvements in Diabetic Status for Patients Receiving an Angiotensin-II Receptor Blocker
Authors: Tatsuaki Murakami, Kazuo Ohsato
Journal: Circulation (2009)

Background: Effects of insulin sensitizing agents on coronary artery pathophysiology have marked attention, but the long-term effects remain uncertain. We previously reported clinical effects of thiazolidinedione, and adverse prognostic impacts of vasomotor dysfunction in coronary arteries. This study evaluated long-term effects of thiazolidinedione, an insulin sensitizer, on vasomotion of coronary arteries frequently affected by diabetes mellitus, in patients treated with an angiotensin-II receptor blocker, one of the best possible antiatherosclerotic therapies. Methods: Twenty-two type-2 diabetic patients treated with an angiotensin-II receptor blocker, were randomized where they received troglitazone (400mg/ day) or pioglitazone (30mg/day) (group-T), or they received therapy without thiazolidinedione for more than 1 year (group-C). We measured reactive changes in coronary blood flow (coronary flow reserve: CFR) or reactive endothelium-dependent dilatation (FMD) of coronary arteries to infusion of ATP (50 μ g) into the study (normal or minimally diseased) left coronary artery. CFR (maximal hyperemic flow-baseline flow/baseline flow) was quantified by coronary angiography and intracoronary doppler-guidewire. Changes in CFR and FMD were compared between the 2 groups. Results: All the enrolled patients manifested good compliance to the treatment and there were improvements in some of metabolic variables in group-T (n=11). CFR increased in group-T (p=0.027) but not in group-C (p=0.102). FMD also increased in group-T (p&lt;0.001), while it remained unchanged in group-C (p=0.768). Changes of CFR or FMD did not correlate to those of HbA1c (CFR: r=0.19, p=0.66, FMD: r=0.15, p=0.80). Conclusion: This study suggests that long-term thiazolidinedione use improves vasomotion of coronary arteries irrespective of glucose metabolic status, which may have beneficial potentials for management of coronary artery disease with type-2 diabetes mellitus.
Abstract 4175: Isoflavone Does not Acutely Alter Endothelial Function in Patients with Cardiovascular Diseases
Authors: Yap-Hang Chan, Kui-Kai Lau, Kai-Hang Yiu, Sheung-Wai Li, Xiao-Ou Shu, Hung-Fat Tse, Chu-Pak Lau
Journal: Circulation (2006)

Introduction: Prior in-vitro studies demonstrated a stimulatory effect of isoflavone on the endothelial nitric-oxide synthase system within a period of 48–96 hours, and may lead to an improvement in vascular endothelial function. However, the acute effect of high dose intake of isoflavone on endothelial function in patients (pts) with cardiovascular disease remains unclear. Methods: We studied the effect of high dose intake of isoflavone on vascular endothelial function in pts with cardiovascular diseases. 32 pts with ischemic stroke were randomized to receive either 80mg/day isoflavone (n=15) or placebo (n=17) for 3 days. Brachial endothelial function was assessed to determine flow-mediated dilation (FMD) and nitroglycerin-mediate dilation (NMD) at baseline and after treatment using high resolution ultrasound. Results: As shown in Table , there were no significant differences in the mean changes in heart rate, systolic (SBP) and diastolic blood pressure (DBP) in both groups. Furthermore, there were no significant changes in FMD and NMD after 3 days treatment of isoflavone Conclusion: High dose intake of isoflavone (80mg/day) does not acutely alter vascular function in patients with ischemic stroke. Table: Mean Change in Parameters After Isoflavone Treatment
Abstract 5263: Renin Angiotensin System Plays a Crucial Role in the Development of Myocardial Ischemia/Reperfusion Injury With a Condition of Renal Failure in Mice
Authors: Jun-ichi Suzuki, Masahito Ogawa, Yasunobu Hirata, Ryozo Nagai, Mitsuaki Isobe
Journal: Circulation (2009)

Background: The clinical relationship between the heart and renal diseases has been clarified. Although renin angiotensin system (RAS) mediates the development of cardio-renal syndrome, little is known about the etiology obtained from experimental models with myocardial ischemia and renal failure. Methods: To test the hypothesis that RAS plays a pivotal role in cardio-renal syndrome, we developed a novel murine cardio-renal disease model using both the 5/6 subtotal nephrectomy (NTX) and the myocardial ischemia/reperfusion injury (I/R) techniques. Four weeks after the subtotal nephrectomy, the left coronary artery was occluded for 60 minutes followed by 24 hour reperfusion. Results: Serum creatinine levels on day 28 were higher in the NTX group (0.28±0.04 mg/dl, n=8) compared to those in the non-NTX group (0.13±0.01 mg/dl, n=5, p&lt;0.05). The infarction area/area at risk ratio significantly increased in NTX+I/R mice (50.7±5.9 %, n=7) compared to the non-NTX+I/R mice (20.8±3.1 %, n=8, p&lt;0.05), while ischemic area/whole myocardial area was comparable between the two groups. The NTX+I/R hearts had significantly larger left ventricular diameters compared with that of the non-NTX+I/R mice. The number of infiltrating cells was enhanced by the NTX+I/R, while they were limited in non-NTX+I/R. Interstitial fibrosis also increased in NTX+I/R, while non-NTX+I/R suppressed this change. The hearts isolated from NTX+I/R mice increased the mRNA expression ratios (the NTX-IR group per the native group) of angiotensin-converting enzyme (1.57±1.26) and angiotensin II receptor type 1 levels (1.21±0.07) measured by quantitative RT-PCR. Conclusion: RAS deeply involves the development of cardio-renal syndrome and it may have a clinical usefulness in the treatment of myocardial ischemia with renal dysfunction.
Abstract 4934: CLI-Bright: A Phase I Randomized Blinded Clinical Trial Comparing the Effect of Intramuscular Injection of Autologous Bone Marrow Derived Aldehyde Dehydrogenase Bright Cells and Mononuclear Stem Cells in Patients With Critical Limb Ischemia
Authors: Emerson C Perin, Guilherme V Silva, Nicolas Chronos, Robert G Mitchell, Farrell O Mendelsohn, Amir Gahremanpour, Yi Zheng, John Canales, Marlos R Fernandes, Sandi Shaw, Deirdre Smith, Maria G Cabreira, Laurence H Keller, James T Willerson, Brian H Annex
Journal: Circulation (2009)

Background: Critical limb ischemia (CLI) is an advanced stage of peripheral arterial disease (PAD) associated with high morbidity and mortality. Functional improvement and lower amputation rates have been reported in clinical studies using intramuscular (IM) injection of autologous bone marrow mononuclear cells (ABMMNC) into ischemic limbs. Aldehyde Dehydrogenase-Bright (ALDH br ) cells are a highly potent subpopulation of ABMMNC and preclinical studies suggest that ALDH br cells may contribute more effectively to angiogenesis. Therefore, we investigated the safety and efficacy of ALDH br compared to ABMMNC in CLI patients who were not candidate for revascularization. Methods: 21 patients (mean age 72, 13 men) with ankle-brachial index (ABI) &lt; 0.5 and Rutherford category (RC) 4 – 5, were randomized to receive 10 IM injections of either ALDH br cells (n=11) or ABMMNCs (n=10) into the gastrocnemius muscle of the affected limb. Primary outcomes at 3 months were safety and efficacy based on ABI, transcutaneous partial pressure of oxygen (tcPO 2 ), RC, and ischemic ulcer grade. Paired t-test or Wilcoxon sign test was used for statistical analysis. Results: The mean number of ALDH br cells and ABMMNCs implanted were 1.33 × 10 6 and 1.207 × 10 6 . There were no significant clinical differences between the two groups at baseline. There was no adverse reaction to IM injections. One amputation occurred in each group. One death occurred in ALDH br patients, which was not related to the therapy. At 3 months in ALDH br group, ABI and RC improved 0.14 (p=0.025) and 0.64 (p=0.04), respectively. In the ABMMNC group, there were non significant changes in ABI and RC (0.08 and 0.67, respectively). No significant changes from baseline were noted in tcPO 2 and ischemic ulcer grade in either group. Conclusion: IM implantation of ALDHbr cells appears to be safe and our efficacy measures will be the first to compare selected from unselected cells in treatment of critical limb ischemia. Table: ABI, RC and tcPO2 in both groups
Abstract 5166: Inhibition of Pro-inflammatory Cytokine Light Reduces Atherosclerotic Lesion Development in Apo E <sup>−/−</sup> Mice
Authors: Mohammad Akhavanpoor, Christian Erbel, Vijay Shankar, Sultan Celik, Felix Lasitschka, Hugo A Katus, Thomas J Dengler
Journal: Circulation (2009)

Atherosclerotic plaque typically contains infiltrates of activated macrophages and T cells. We previously showed higher levels of LIGHT in human carotid artery plaque tissue samples of symptomatic (TIA, Stroke) compared to asymptomatic patients. Effects of inhibition of the pro-inflammatory cytokine LIGHT on atherosclerosis development was studied in a rodent model. 30 male apoE −/− mice fed a western diet were treated either with an adenoviral vector, containing the gene sequence for a fusion protein of the extracellular part of the LIGHT receptor molecule TR2 linked with the Fc part of human IgG1 (AdmTR2hIgG), acting as a specific blocking agent against LIGHT (3×10 9 infection units, tail vein injection) (n=10) or an adenoviral vector containing GFP-gene sequence only (AdGFP, sham) (n=10) or mice receiving sodium chloride (untreated group) (n=10). After 8 weeks aortic root was embedded in OCT and serially cryosectioned in 5 μ m intervals. Sections every 75 μ m were stained with Oil RedO, the lesion area was quantified using PC-based image analysis. Inhibition of LIGHT by AdmTR2hIgG markedly reduced atherosclerotic plaque volume (p=0.001) and maximum stenosis (p=0.001) compared to the untreated group or AdGFP treated mice (sham). Analysis of peripheral blood and spleen cells revealed no significant alterations in composition of immune cell compartments or cellular activation status. Immunohistochemistry revealed significant reduction of cellular infiltration by T cells and macrophages as well as T cell- and macrophage density (cell number/lesion area) in atherosclerotic lesions in AdmTR2hIgG compared to untreated/sham mice. Functional blockade of the pro-inflammatory cytokine LIGHT reduced atherosclerotic lesion development in apoE −/− mice without major derangement of peripheral cellular immunity. Our findings suggest a relevant role for LIGHT in atherosclerosis warranting further study of pathogenic mechanisms and therapeutic potential.
Abstract 4887: The Thiazolidinedione Pioglitazone up-regulates Vascular Telomere Regulating Proteins and Prevents Cellular Senescence in Mice
Authors: Christian Werner, Janine Pöss, Christoph Gensch, Michael Böhm, Ulrich Laufs
Journal: Circulation (2009)

Background: PPAR- γ agonists (thiazolidinediones, TZDs) are used for the treatment of diabetes mellitus. Experimental and clinical data implicate that TZDs may mediate vascular effects in addition to the lowering of blood glucose. Aging is the predominant risk factor for the development of cardiovascular disease. Telomeres and telomere-associated proteins affect cellular aging, senescence and survival. We hypothesized that TZDs may regulate vascular telomere biology. Methods and Results: C57/Bl6 mice (Age 12 weeks, male) were subjected to treatment with pioglitazone (20mg/kg i.p. daily) or vehicle for 4 weeks. Telomere repeat amplification protocol (TRAP) assays showed a marked increase in aortic telomerase activity in the pioglitazone group to 319±30% vs. vehicle. Western blots demonstrated an increased protein levels of telomere-repeat binding factor 2 (367±20%) and reduced expression of the senescence- and apoptosis-related factors p16 (65±11%) and p53 (53±28%). Similar observations were made in mononuclear cells isolated from the spleen. Additionally, the number of spleen-derived endothelial progenitor cells was up-regulated in TZD-treated mice (550±36%). The physiologic significance of these findings was tested by induction of vascular oxidative stress in-vivo by injection of lipopolysaccharide (LPS, 125mg, i.p.). Endothelial apoptosis in the thoracic aorta was quantitated by hairpin oligonucleotid assays. LPS increased apotosis to 576±16 % of vehicle which was potently prevented in TZD-treated animals (Pio+LPS 241±12 %). All reported effects were significant with p&lt;0.05, n = 6 –12 per group. Conclusions: TZD treatment up-regulates telomerase activity, telomere-capping proteins and induces anti-senescent effects in the vascular wall. The reduction of LPS-induced endothelial apoptosis indicates that the observed effects are physiologically relevant in mice. Our data improve the molecular understanding of the vascular effects of TZDs.