tbuckley/cabot-search huggingface dataset:
Abstract 4964: Tnf- <i>α</i> Antagonists Improve Arterial Stiffness in Patients With Inflammatory Arthropathies: Results From a One Year Controlled Study
Authors: Kristin Angel, Sella Provan, Tore K Kvien, Dan Atar
Journal: Circulation (2009)

Introduction: The chronic inflammatory state of rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) contributes to the accelerated atherosclerosis associated with these diseases. Hypothesis: We assessed the hypothesis that one year treatment with TNF- α antagonists would improve arterial stiffness in patients with RA, AS and PsA. Methods: A total of 52 patients with RA, AS or PsA and clinical indication for anti-TNF- α therapy were included. 36 patients started with anti-TNF- α therapy and were compared with a non-treatment group of 16 patients. Aortic pulse wave velocity (aPWV) and augmentation index (AIx) were measured at baseline and after one year (Sphygmocor). Each visit also included blood samples and assessment of disease activity. Results: Values are given as mean± SD. Age of the patients in the treatment/control group was 46.2±12.2/49.0±14.1 years (p=0.21), 42.9/50.0 % (p=0.63) were females and disease duration was 11.0±9.6/11.6±10.1 years (p=0.56). Patients who started anti-TNF- α therapy had a significant decrease in aPWV (−0.53±0.13 m/s) whereas the patients in the control group had no change (+0.08±0.10 m/s, p=0.001 for between groups changes). Between groups differences for AIx were not observed (change 0.1±6.1 % and 0.2±5.7 %, p=0.95). There was no change in blood pressures, lipid levels or kidney function in any of the groups. A significant reduction in CRP and DAS28 (RA patients) was observed in the treatment group, but we did not find any significant bivariate correlations between the changes in aPWV and CRP ( ρ =0.11, p=0.55) or between changes in aPWV and DAS28 in the RA group ( ρ = −0.21, p=0.44). Conclusion: The present study shows for the first time in a comparative design that long term anti-TNF- α therapy improves aPWV in patients with RA, AS and PsA. This finding supports the idea that atherosclerosis is partly driven by inflammation, and that this process is amenable to pharmacologic intervention. Baseline value and change in key variables
Abstract 5103: Perivascular Adipose Tissue in Angiotensin II Dependent Hypertension
Authors: Tomasz J Guzik, Louise McCann, Heinrich Lob, Tomasz Mikolajczyk, Klaudia Budzyn, Marek Naruszewicz, David G Harrison
Journal: Circulation (2009)

Recent studies have suggested that perivascular adipose tissue (pvAT) is not just a mechanical scaffold for the vasculature but that it plays a critical role in vascular disease. The effects of mediators such as angiotensin II on perivascular adipose tissue however remain unknown. Accordingly, we examined the effects of chronic (14 day) angiotensin II (490ng/kg/min) infusion in mice on perivascular adipose tissue in comparison to effects on visceral (VAT) and subcutaneous (SAT) adipose tissue. Real time PCR and Western blotting showed that both AT1R and AT2R angiotensin II receptors were expressed in all studied compartments of AT but were greater in pvAT (485±90 vs. 45±18 in VAT and 3±0.7 in SAT U/ug RNA for AT1R mRNA; p&lt;0.001). Angiotensin II infusion decreased epidydymal fat pad weight (413±45 mg vs 181±23mg; p&lt;0.01) with concomitant increase of perivascular fat measured histologically (18±3 vs. 30±6 AU per aortic lumen; p&lt;0.01). Interestingly, the cellularity of both pvAT and VAT increased (pvAT&gt;&gt;VAT) significantly but remained unchanged in SAT upon Angiotensin II infusion. Angiotensin II significantly altered adipocytokine expression in pvAT and VAT but not in SAT. Resistin levels increased in pvAT in response to angiotensin II, while leptin, visfatin and adiponectin decreased. The most significant changes were observed in inflammatory cytokines and chemokines. IL-6, TNF-a, IL-17A and were induced in pvAT to a greater degree than in VAT and were not changed by angiotensin II in SAT. Angiotensin II increased RANTES mRNA 6-fold in pvAT but not in VAT or SAT. Immunohistochemistry confirmed an increase in RANTES expression selectively in pvAT. These changes of cytokine and chemokine expression were accompanied by increased infiltration of pvAT with T lymphocytes expressing the RANTES receptor CCR5. These data indicate that angiotensin II affects adipocytokine and cytokine expression in adipose tissue and these effects are most pronounced in pvAT leading to T cell infiltration. These data indicate that the pvAT is a unique compartment of fat predisposed to angiotensin II-induced inflammation and a potential target for therapeutic intervention.
Abstract 5198: Histamine H1 Receptor Promotes Atherosclerotic Lesion Formation by Increasing Vascular Permeability for Low Density Lipoproteins
Authors: Izabela Rozenberg, Lucia Rohrer, Susanna H Sluka, Janin Hofmann, Burkhard Becher, Jorge Soliz, Pavani Mocharla, Alexander Akhmedov, Jan Borén, Jan Steffel, Takeshi Watanabe, Thomas F Luscher, Felix C Tanner
Journal: Circulation (2009)

Enhanced endothelial permeability with intimal accumulation of low density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Here we demonstrate that ApoE −/− mice treated with a histamine H1, but not H2 receptor antagonist developed 40% less atherosclerotic lesions in the aorta than placebo treated controls. Similarly, genetic deletion of the H1, but not H2 receptor resulted in 60% reduction of lesions compared to ApoE −/− controls. The H1 receptor enhanced permeability for LDL and lipid accumulation in aorta, whereas plasma lipoprotein levels remained unaffected. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor on vascular cells, while its presence on bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine CCL5 and higher numbers of macrophages and lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. These observations indicate that H1, but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation.
Abstract 4884: Identification of Hetero-multimeric P2X Receptor Which Regulates Vascular Tone in Rat Arterial Smooth Muscle
Authors: Megumi Sugihara, Hiromitsu Morita, Miho Matsuda, Shunichi Kajioka, Yushi Ito, Kihachiro Abe, Masato Hirata
Journal: Circulation (2009)

Background: ATP is one of important vasoactive substances and is released from sympathetic nerve terminal, endothelial cells and other cells surrounding smooth muscle cells. Ionotropic P2X channel is one of the representative receptors, and only homomeric P2X 1 has been thought to be the functional molecular architecture in vascular smooth muscle cells for a long time. However, some inconsistencies exist between native P2X 1 -like and cloned P2X 1 channels. Methods: Male rats aged 10 –11w were used. P2X channel current was measured in smooth muscle cells isolated from aorta, cerebral or mesenteric artery using patch-clamp technique. RT-PCR and Western blot analyses were employed for detecting their messenger RNAs and proteins, and their interaction in combination with an immunoprecipitation method. Results: Application of ATP (≥100nM) elicited dual phase, fast and slow, desensitizing inward current by whole cell recording. The ATP-induced current also showed rebound current, which is a typical feature specific to cloned P2X 1/5 channel. I-V relationship of the current was that of inward-rectifying, and reversal potential was around 0mV, close to the equivalent potential of non-selective cation channel in spite of various intracellular chloride ion concentration. Sensitivity of several ATP analogs is as follows; 2-methylthio ATP&gt;BzATP&gt;ATP&gt; α , β -methylene ATP&gt;ATP γ S. The channel conductance was 10.5±0.1pS by a single channel recording. The current was blocked by several P2X and P2 receptor antagonists, TNP-ATP, suramin and PPADS, and their 50% inhibitory concentrations (IC 50 ) were similar to those of cloned P2X 1/5 channel (1.0, 0.5 and 0.6 μ M, respectively; n=3~5). RT-PCR and Western blot analysis revealed highly expression of both P2X 1 and P2X 5 channels in extracts from arteries examined, and both channel proteins were found to be complexed as assessed by an immunoprecipitation method. Conclusion: Our results indicate that hetero-multimeric P2X 1/5 channel, but not only P2X 1 , is functionally expressed in arterial smooth muscle, and may play an important role in vascular tone regulation.
Abstract 4890: Telmisartan Decreases Sympathetic Nerve Activity via Reduction in Oxidative Stress Through the Blockade of AT1 Receptor in the Vasomotor Center in Dietary-induced Obesity Rat
Authors: Satomi Konno, Yoshitaka Hirooka, Takuya Kishi, Kenji Sunagawa
Journal: Circulation (2009)

Background: Activation of sympathetic nerve activity (SNA) is critically involved in the occurrence of hypertension in metabolic syndrome (MetS). However, the mechanism(s) involved remains unknown. Reactive oxygen species (ROS) generation in the brain may elicit sympathoexcitation in MetS. The rostral ventrolateral medulla (RVLM) is the vasomotor center that determines basal central sympathetic outflow. ROS in the RVLM is produced mainly by NAD (P) H oxidase via angiotensin II type 1 receptor stimulation (AT 1 R). The present study aimed to determine whether telmisartan decreases SNA via a reduction in ROS through the blockade of AT 1 R in the RVLM of MetS model rats. Methods and Results: Male Sprague-Dawley rats were fed a high-fat diet and segregated into obesity-prone (OP, n = 5) and obesity-resistant (OR, n = 5) groups based on their body weight (BW) after 13 weeks. The OP group was then divided into 2 groups, OP with telmisartan (5mg/kg/day for 12 weeks, TLM-OP, n = 3) and OP without telmisartan (VEH-OP, n = 3). At 13 weeks, body weight (BW), systolic blood pressure (SBP), heart rate (HR), and urinary norepinephrine excretion (uNE) as a parameter of SNA were significantly higher in OP than in OR (BW; 760 ± 46g vs 548 ± 13g, SBP; 151 ± 5mmHg vs 123 ± 7mmHg, HR; 375 ± 11bpm vs 333 ± 5bpm, uNE; 0.35 ± 0.05 μ g/day/kg vs 0.25 ± 0.04 μ g/day/kg, n = 5 for each, P &lt; 0.05 for each). ROS in the RVLM, measured by the thiobarbituric acid-reactive substances (TBARS) method, was significantly higher in OP than in OR (7.2 ± 0.8 μ mol/g vs 2.2 ± 1.9 μ mol/g wet wt, n = 4 each, P &lt; 0.05). Microinjection of AT 1 R blocker (ARB), candesartan, into the RVLM induced a significantly greater mean SBP reduction in OP than in OR. The expression of angiotensinogen, angiotensin-converting enzyme (ACE), and AT 1 R in the RVLM assessed by Affymetrix microarray was significantly higher in OP than in OR. TLM-OP had significantly lower BW, SBP, HR, uNE, and TBARS than VEH-OP. Microinjection of angiotensin II into the RVLM resulted in significantly lower pressor responses in TLM-OP than in VEH-OP. Conclusion: In MetS, increased ROS in the RVLM produced by upregulation of the local renin-angiotensin system increases SNA. Telmisartan inhibits SNA via a reduction of ROS through the blockade of AT 1 R in the RVLM.
Abstract 5214: Microvascular Obstruction as Prognostic Marker for Long-Term Outcome After ST-Elevation Myocardial Infarction Compared to Traditional Prognostic Markers
Authors: Suzanne de Waha, Johannes Zachrau, Ingo Eitel, Matthias Gutberlet, Gerhard Schuler, Holger Thiele
Journal: Circulation (2009)

Background Microvascular obstruction (MO) assessed by magnetic resonance imaging (MRI) has been shown to be a prognostic marker for combined clinical endpoints (including unstable angina and repeat target vessel revascularization) after ST-elevation myocardial infarction (STEMI) in a very limited number of patients. If MO gives also prognostic information for “hard” endpoints and whether MO adds information independent of traditional prognostic markers and scores has not been investigated, yet. Methods and Results STEMI patients reperfused by primary PCI (n=408) underwent contrast-enhanced-MRI 4±7 days after the index event. Clinical follow-up was conducted after a mean of 18±11 months. The primary endpoint was defined as composite of death, non-fatal myocardial reinfarction and congestive heart failure. Secondary outcomes included the individual components of the composite endpoint. In 71% (n=286) MO was present. The composite clinical endpoint occured more frequently in patients with MO compared to patients without MO (19.6 vs. 6.7%, p=0.001). MO presence showed a trend towards higher occurrence of death (7.0 vs. 2.5%, p=0.09), reinfarction (5.6 vs. 1.7%, p=0.09) and congestive heart failure (7.0 vs. 2.5%, p=0.09). In a multivariate cox regression analysis including all parameters significant in univariate analysis (TIMI risk-score, Killip-class, ST-resolution, post-PCI TIMI-flow, infarct size, left-ventricular ejection fraction, endsystolic volume, age and diabetes mellitus), MO remained significantly associated with the occurrence of the composite endpoint (p=0.04). Apart from MO only post-PCI TIMI-flow (p=0.03), diabetes (p=0.03) and age (p=0.05) remained significant predictors for the combined clinical endpoint. The strongest predictor for the occurrence of the combined clinical endpoint was MO (OR 2.5; 95%CI 1.1–5.9), followed by post-PCI TIMI-flow (OR 2.3 95%CI 1.1– 4.9), diabetes (OR 1.8 95%CI 1.1–3.1) and age (OR 1.8 95%CI 1.0 –3.2). Conclusion Compared to traditional prognostic markers and scores, MO is the strongest predictor for the occurrence of death, non-fatal myocardial reinfarction and congestive heart failure after STEMI. Thus, cardiac MRI adds important information regarding post-infarction prognosis.
Abstract 5207: Role of Endothelial Nitric Oxide Synthase in Endothelial Cell Mitochondrial Biogenesis and Stress Adaptation
Authors: Chunying Li, John F Keaney
Journal: Circulation (2009)

Activation of metabolic stress pathways is known to confer stress adaptation and promote longevity in lower organisms. We have recently found that chronic stimulation of AMP-activated protein kinase (AMPK) in endothelial cells promotes both mitochondrial biogenesis and stress adaptation that prevent hypertension-induced endothelial dysfunction. However, the precise mechanisms for endothelial cell mitochondrial biogenesis and stress adaptation are not well defined. To this end, we chronically activated AMPK with 5-aminoimidazole-4-carboxamide riboside (AICAR) and observed enhanced mitochondrial biogenesis in wild-type mouse endothelium as determined by mitochondrial-specific fluorescence (Mitotracker green) and protein expression (cytochrome c and SOD2). In contrast, endothelium from eNOS-null mice exhibited no mitochondrial biogenesis in response to AICAR and this defect was rescued by reintroduction of eNOS by adenoviral-mediated gene transfer. Moreover, eNOS appeared critical for stress adaptation as chronic AMPK stimulation attenuated H 2 O 2 -induced cell death in wild type, but not eNOS-null endothelium. To test this pathway in vivo , we used 20-hydroxy-eicosatetraenoic acid (20-HETE) administration to induce endothelial dysfunction measured as prostacyclin-dependent, acetylcholine-induced arterial relaxation. We found that 20-HETE produced equivalent endothelial dysfunction in both wild-type and eNOS-null mice. However, chronic AICAR administration was able to prevent 20-HETE-induced dysfunction in wild-type, but not eNOS-null mice. Thus, these data indicate that eNOS is involved in AICAR-induced mitochondrial biogenesis and stress adaptation in endothelial cells. These results have implications for targeting stress adaptation as a means to prevent endothelial dysfunction and potentially ameliorate vascular disease.
Abstract 5437: Pluripotent Stem Cells Induced From Adult Somatic Cells by Dedifferentiation Without Genetic Manipulation
Authors: Choon Soo Lee, Hyun-Jai Cho, Yoo-Wook Kwon, Jae Seung Paek, Sun-Hee Lee, Sun-Young Jo, Jin Hur, Eun Ju Lee, Hyun-Jae Kang, Byung-Hee Oh, Young-Bae Park, Hyo-Soo Kim
Journal: Circulation (2009)

Background: Reprogramming of somatic cells into pluripotent stem cells have opened the new-era in regenerative medicine. Viral transduction of defined factors successfully achieved pluripotency from mouse and human somatic cells. However, in the generation process of induced pluripotent stem (iPS) cells, genetic integration of certain factors may cause mutagenesis or tumorigenicity, which hampers further application for cell therapy. Methods and Results: We investigated that the transient cellular delivery of mouse ES cell-derived proteins enables dedifferentiation of mouse somatic cells into pluripotent stem cells without genetic manipulation. We found that transient delivery of ES cell-derived proteins using reversible permeabilisation can activate endogenous transcription factors related pluripotency. Dedifferentiated somatic cells are morphologically indistinguishable from the authentic ES cells. In the process, the methylation and histone modification status in the promoter regions of pluripotency-related genes are converted from somatic to ES-equivalent statues. Molecular biologically, the patterns of global gene expression, genomewide ChIP sequencing and proteomics using Itracq are very similar to those of protein donor ES cells. Functionally, dedifferentiated cells form embryoid body (EB) structures in suspension culture. On 7 days of re-differentiation, cells contract spontaneously and express cardiac troponin T and α -sarcomeric actinin, indicating the properties of cardiomyocytes. And also the certain portions of re-differentiated cells express ectoderm, mesoderm and endoderm proteins. Furthermore, dedifferentiated cells possess in vivo differentiation and developmental potentials including well-differentiated teratoma formation, contribution to chimeras and germline transmission. Conclusions: These results demonstrate that transient delivery of ES cell-derived proteins can induce dedifferentiation of adult somatic cells into pluripotent stem cells. Our results provide an alternative and safe strategy for dedifferentiation or reprogramming of adult somatic cells and may facilitate tailored- or patient-specific pluripotent stem cell-derived cell therapy.
Abstract 4858: Is Brachial Artery Diameter an Early Index of Organ Damage in Hypertension?
Authors: Giuseppe Schillaci, Giacomo Pucci, Massimo R Mannarino, Matteo Pirro, Leonella Pasqualini, Gaetano Vaudo, Elmo Mannarino
Journal: Circulation (2009)

Objectives: Arteries can enlarge in response to a variety of hemodynamic and non-hemodynamic stimuli. The role of vascular remodeling in atherosclerosis-free arteries in hypertension is poorly understood. We investigated whether brachial artery diameter (BAD), an index of vascular remodeling, is increased in hypertensive patients, and has a relationship with left ventricular (LV) mass, an important marker of target-organ damege in hypertension. Methods: 463 never-treated subjects with uncomplicated essential hypertension (283 men, 180 women; age 48+/−11 years, office blood pressure 155/96+/−17/9 mmHg) underwent M-mode echocardiography, 24-h BP monitoring, and ultrasound assessment of end-diastolic non-dominant BAD. 96 healthy normotensive subjects (40% women) served as controls. Analyses were performed separately in men and women. Results: BAD had significant direct associations with age, male sex, systolic blood pressure and body mass index. BAD was larger in hypertensive subjects than in normotensive controls (4.62+/−0.8 vs 4.48+/−0.7 mm, p=0.02). In hypertensive subjects, age-adjusted BAD values were higher in subjects with LV hypertrophy (LV mass &gt;51 g/m2.7; 4.46+/−0.6 vs 4.04+/−0.6 mm in women, 5.13+/−0.7 vs 4.81+/−0.7 mm in women, both p&lt;0.0001). In sex-specific multiple linear regression analyses (Table), BAD predicted LV mass index in both men (beta=0.17, p=0.003) and women (beta=0.13, p=0.043), independently from the effects of age, 24-hour BP and body mass index (all p&lt;0.05). Conclusion: Diameter of the brachial artery is increased in untreated hypertensive subjects. In hypertension, larger brachial artery diameter is associated with left ventricular hypertrophy, and this relation is partly independent from the effect of common predictive factors. Brachial artery diameter is a potential early marker of organ damage in hypertension.
Abstract 5462: Dual Effects of Nox2-NADPH Oxidase During Atherosclerotic Plaque Development in Apolipoprotein E-Null Mice
Authors: Courtney P Judkins, Henry Diep, Brad R Broughton, Anja E Mast, Elizabeth U Hooker, Alyson A Miller, Stavros Selemidis, Gregory J Dusting, Christopher G Sobey, Grant R Drummond
Journal: Circulation (2009)

The reactive oxygen species (ROS) -producing NADPH oxidases are implicated in atherogenesis, although the relative contribution of the different isoforms of these enzymes to plaque development has not been established. We investigated the role of the ‘classical’ Nox2-containing NADPH oxidase in atherogenesis in apolipoprotein E-null (ApoE −/− ) mice. Nox2 expression (Western blotting) and localisation (immunohistochemistry), ROS production (L012-enhanced chemiluminescence), nitric oxide (NO) bioavailability (isometric contractions to N γ -nitro-L-arginine methyl ester) and atherosclerotic lesion development along the luminal surface of the aorta and in the aortic sinus, were measured in 12, 19 and 26 week-old wild-type, ApoE −/− and Nox2 −/− /ApoE −/− mice maintained on a Western style diet (21% fat, 0.15% cholesterol). Nox2 expression was elevated in the endothelium of ApoE −/− mice prior to lesion formation and this was associated with elevated ROS production. In developing plaques, macrophages were also a source of Nox2. The absence of Nox2 in 12 and 19 week-old Nox2 −/− /ApoE −/− mice had minimal effects on plasma lipids but was associated with a marked reduction in vascular ROS production and an increase in NO bioavailability. En face lesion coverage of the aorta from the arch to the iliac bifurcation was also markedly reduced in 12 and 19 week-old Nox2 −/− /ApoE −/− versus ApoE −/− mice. However, in 26 week-old mice, differences in en face lesion area were no longer apparent between strains and, surprisingly, intimal thickening in the aortic sinus was more pronounced in the Nox2 −/− /ApoE −/− mice. Thus, we have described, for the first time, that Nox2-NADPH oxidase plays dual roles in atherosclerotic plaque development in ApoE −/− mice, being pro-atherogenic in early stages, and possibly protective in later stages of the disease.