tbuckley/cabot-search huggingface dataset:
Abstract 5512: Vascular Rhexis: A Potentially Modifiable Contributor to Negative Remodeling After Myocardial Infarction
Authors: Akm Tarikuz Zaman, Christopher J French, Burton E Sobel
Journal: Circulation (2009)

We previously noticed in studies of plasminogen activator inhibitor type-1 (PAI-1) knockout (PKO) mice that infarction was often hemorrhagic. Thus, we hypothesized that the intensified fibrinolysis was unmasking a loss of integrity of coronary vessels (vascular rhexis) potentially caused in part by inflammation. To test this hypothesis, in the present study we induced myocardial infarction (MI) in PKO and control C57BL6 mice by ligation of the left coronary artery for 48 hr, harvested the hearts for assessment of infarct size (measured based on depletion of left ventricular [LV] creatinine kinase activity), and quantified hemorrhage by assaying with non-cross reacting ELISAs hemoglobin content corrected for myoglobin content in LV myocardium. Normal mouse LV myocardium contains approximately 40 μ l blood/g. PKO mice (n = 9) had marked intramyocardial hemorrhage in infarct zones (432±27 SEM μ l blood/g). Vascular rhexis was evident in C57BL6 controls as well (n = 5) as judged from the presence of 51±3 μ l blood/g LV 48 hr after coronary occlusion despite less blood in the infarct zone within 4 hr after coronary occlusion (10±5 μ l blood/g, n = 13). Intramyocardial hemorrhage in PKO mice was significantly reduced (302±37 μ l blood/g, p &lt; 0.01 vs control PKO) by treatment with cyclophosphamide (n = 12) before coronary occlusion sufficient to induce profound leukopenia and by treatment with aprotinin (n = 9) after coronary occlusion to inhibit plasmin (220±40 μ l blood/g, p &lt; 0.01 vs control PKO). Treatment with the combination of both (n = 4) virtually eliminated hemorrhage (49±5 μ l blood/g, p &lt; 0.01 vs control PKO). Treatment did not modify infarct size (PKO: 46±2% of LV mass; PKO with cycloposphamide: 45±1%; PKO with aprotinin: 43±2%). Thus, rupture of coronary vessels occurs within 48 hr after the onset of coronary occlusion leading to hemorrhage that may exacerbate late, negative ventricular remodeling; cyclophosphamide reduces vascular rhexis by attenuating inflammation; and aprotinin reduces hemorrhage associated with vascular rhexis unmasked by intensified fibrinolysis by inhibiting plasmin.
Abstract 5630: Identification of Adventitial Hematopoietic Progenitor Cells in Normal and Atherosclerotic Murine Aortas
Authors: Adriana Harbuzariu, Tyra A Witt, Laurel S Kleppe, Eric W Holroyd, Lisa L Nesbitt, Cheryl S Mueske, Allan B Dietz, Rajiv Gulati, Gurpreet S Sandhu, Robert D Simari
Journal: Circulation (2009)

Background: Hematopoietic stem cells and the vasculature share a unique relationship during development, in the adult bone marrow and in the setting of extramedullary hematopoiesis within diseased calcified vessels. We hypothesized that the adult vasculature may contain progenitor cells with the capacity to reconstitute multi-lineage hematopoietic cells. Methods: Aortas from normal and ApoE −/− adult mice were disaggregated with collagenase and elastase. Disaggregates were cultured in methylcellulose for quantification of short and long term hematopoietic colony forming units (CFU). Flow cytometry assessed various populations of hematopoietic progenitor cells. Aortic disaggregates (or bone marrow or blood) from ROSA26 and GFP mice were transplanted into sublethally irradiated C57BL/6 recipients (n=6) via tail vein injections. Bone marrow cells from the primary recipients were transplanted at 4 months to secondary C57BL/6 recipients (n=6). Mice were sacrificed 3 months later. Blood and bone marrow were analyzed. Results: In short term culture in methylcellulose, aortic disaggregates generated erythroid, macrophage, granulocyte and megakaryocyte CFU, with predominance of macrophage colonies, primarily from adventitia (p&lt;0.05) and a greater frequency was found in Apo E −/− mice (p&lt;0.05). Long term culture defined that the combined frequency of the hematopoietic precursors approximates the frequency found in bone marrow (1:47,277). Flow cytometry of the aortic disaggregates indicates that among lin-/c-kit+/sca-1+ cells a small population of hematopoietic stem cells (CD150+endoglin+) and a population of multipotent progenitor cells (CD150− endoglin−) exist. Infusion of aortic disaggregates generated bone marrow, blood and spleen chimerism in primary and secondary transplanted mice at 3– 4 months. Flow cytometry of peripheral cells demonstrated multilineage hematopoietic cells. Conclusions: For the first time, we have identified a variety of progenitor cell populations in the aorta capable of hematopoiesis. Infusion of these cells into sublethally irradiated mice results in stable chimeras. These data support the presence of novel aortic hematopoietic progenitor cells.
Abstract 5559: Lack of Sequestosome1 Accelerates Neointimal Hyperplasia and Carotid Artery Remodeling
Authors: Satoshi Sakai, Eiji Warabi, Rika Sugimoto, Satoru Katayanagi, Toru Yanagawa, Kazutaka Aonuma, Tetsuro Ishii
Journal: Circulation (2009)

The cytoplasmic signal adaptor protein designated sequestosome1 (SQSTM1) (A170 in mouse, ZIP in rat or p62 in human) plays a key role in modulating signal transduction via membrane receptors. SQSTM1 has a UBA ubiquitin-binding domain in the C-terminus and participates in the assembly of ubiquitinated protein aggregates termed sequestosome and modulation of ubiquitination pathways involved in NF- κ B activity and receptor trafficking. We have found that deficiency of SQSTM1 in mice exhibits mature-onset obesity accompanied by insulin and leptin resistance. We previously established that redox sensitive transcription factor Nrf2 upregulates SQSTM1 expression in response to atherogenic stimuli or laminar shear stress in vascular cells, and here examine role of SQSTM1 in neointimal hyperplasia and vascular remodeling in vivo following carotid artery ligation. Neointimal hyperplasia was markedly enhanced at proximal sites of ligation after 3 weeks in SQSTM1−/− (n=10) compared with wild type mice (n=10). The intimal area and stenotic ratio were 2.1- and 1.7-fold higher in SQSTM1−/− mice, respectively, indicating enhanced proliferation of vascular smooth muscle cells (SMCs). When aortic SMCs were isolated from wild type and SQSTM1−/− mice and cultured in vitro, we found that SQSTM1−/− SMCs proliferated more rapidly in response to fetal calf serum (FCS) and attained 2–3-fold higher cell densities compared to wild type SMCs. Moreover, FCS caused a rapid transient down regulation of SQSTM1 in wild type SMCs. Early and late phases of p38MAPK activation in response to FCS stimulation were more enhanced in SQSTM1−/− SMCs, and inhibitors of p38 and ERK1/2 signaling pathways significantly attenuated SMCs proliferation. In summary, SQSTM1−/− mice exhibit enhanced neointimal hyperplasia and vascular remodeling following arterial ligation in vivo. The enhanced proliferation of SQSTM1−/− aortic SMCs in vitro highlights a novel role for SQSTM1 in suppressing smooth muscle proliferation following vascular injury.
Abstract 5520: Upregulation of Arginase I Reduces Nitric Oxide-mediated Coronary Arteriolar Dilation in Patients With Type 2 Diabetes
Authors: Zsolt Bagi, Timea Beleznai, Attila Feher, Gabor Kaley
Journal: Circulation (2009)

We hypothesized that increased expression of arginase I reduces nitric oxide (NO)-mediated coronary arteriolar dilations in patients with type 2 diabetes (2-DM). Arterioles were dissected from right atrial appendages from patients with (N=17) or without (N=14) 2-DM. Coronary arterioles (123±16 μ m) were cannulated, pressurized (80 mmHg) and changes in diameter were measured with videomicroscopy. After spontaneous tone developed, acetylcholine (ACh, 1 nM-1 μ M) elicited dilations of coronary arterioles from patients without 2-DM (max. 82±5%), whereas it induced constrictions of arterioles from 2-DM patients (−41±9%). Dilations to the NO donor sodium nitroprusside were not different in the two groups. Inhibition of NO synthesis with L-NAME reduced coronary dilations in subjects without 2-DM, but did not affect constrictions to ACh in 2-DM patients. In vitro application of L-arginine (3 mM, 30 mins) restored coronary dilations to ACh in 2-DM patients (from −40±9 to 39±6%). Expression of arginase I, as detected by Western immunoblots and immunohistochemistry, was significantly increased in coronary arterioles of 2-DM patients. In conclusion, this study is the first to show that in coronary arterioles of patients with 2-DM arginase I expression is enhanced, which diminishes NO-mediated arteriolar dilation. Our findings allow for the feasibility that L-arginine supplementation may improve coronary endothelial function in patients with type 2 diabetes.Grants: AHA 0735540T and NIH NHLBI 43023. 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 5590: Therapeutic Neovascularization by AAV 2/9-based Gene Transfer of hVEGF-A and hPDGF-b in Chronic Ischemia (Pig and Rabbit Model)
Authors: Achim Pfosser, Rabea Hinkel, Michael Thormann, Corinna Lebherz, Alexander Wuchrer, Franziska Globisch, Chiraz El-Aouni, Andrea Banfi, Peter Boekstegers, Christian Kupatt
Journal: Circulation (2009)

In patients suffering from ischemic cardiomyopathy or peripheral artery disease, lacking interventional or surgical treatment options, induction of neovascularization via vascular growth factor application is a novel therapeutic concept. Here we tested an approach by combining hVEGF-A with hPDGF-B and prolonging the expression period by using a AAV as viral vector. Methods: In rabbits (n=5 per group), 0.5×10 11 rhAAV-VEGF-A with or without 1×10 12 rAAV-hPDGF-B were retroinfused at d7 of femoral artery excision. At d7 and 35 angiography of both hindlimbs was performed for collateral score and frame count score (cinedensitometry, % d7). Capillary/muscle fiber ratio (C/MF) was determined at d35. In pigs, a reduction stent graft was implanted into the circumflex artery (Cx), leading to complete occlusion at day 28, when retroinfusion of rAAV-VEGF-A/PDGF-B ( 2×1012 particles each) or rAAV-LacZ (4×10 12 particles) was performed. Global myocardial function (EF and LVEDP) and regional myocardial perfusion (fluorescent microspheres) were assessed at d28 and d56, were as regional myocardial function was ovbtained at day 56. Results: In rabbits, rAAV-hVEGF-A strongly induced angiogenesis (C/MF 1,32±0,07 vs. 0.96±0,08 in LacZ-controls), but not collateral growth (125±7% d7 vs. 95±6% d7, p=0.09) or perfusion (136±12% vs. 107±9%, p=0.07). hVEGF-A/hPDGF-B co-transfection, however, enhanced collateral growth (146±9%, p=0.01) and perfusion (163±8%, p&lt;0.05) at a similar capillary density (1,44±0,10 CM/F). In the pig model, retroinfusion of rAAV-hVEGF-A/hPDGF-B increased regional myocardial blood flow (1,5±0,1ml/g vs. 1,0±0,1ml/g in mock-transfected controls, p&lt;0.05), based on growth of collaterals (9,5±0,3 vs. 5,5±0,5 in controls, p&lt;0.01) and capillary density (146±8 vs. 66±6/field in controls). rAAV-hVEGF-A/hPDGF-B improved global myocardial function (EF: 48±1% vs. 33±1% in control; LVEDP: 14.7±0.9 vs. 19.6±0.8mmHg in controls, p&lt;0.05) accompanied by an improved regional myocardial function in the RCx area (11±3 % SES vs 2±6 %, controls). Conclusions: Longterm overexpression of hVEGF and PDGF substantially enhanced angiogenesis and arteriogenesis in the ischemic region followed by an improved function, wich is superior to hVEGF alone.
Abstract 5497: Platelet Activation in Patients Undergoing Carotid Artery Stenting Procedure
Authors: Marina Camera, Paola Bogani, Ali S Ghulam, Stefano Galli, Ezio Tirloni, Paola Canzano, Paolo Ravagnani, Marta Brambilla, Elena Tremoli, Piero Montorsi
Journal: Circulation (2009)

Background . Carotid Artery Stenting (CAS) is an evolving method to treat carotid stenosis. A limitation of CAS is the periprocedural risk of temporary or permanent ischemic neurological deficits resulting from local thrombosis and distal embolization. Platelet activation in CAS occurs as a result of vessel wall damage and subendothelium exposure. The dual antiplatelet regimen (aspirin+thienopyridine) has a significant impact on reducing adverse neurological outcomes. Aim . To analyze platelet activation during dual antiplatelet therapy and two months after thienopyridine discontinuation in patients who underwent CAS procedure. Methods . We enrolled 40 patients with high-grade carotid artery stenosis (≥ 70% NASCET criteria). Blood was withdrawn 1 day before (T0), 1 (T1) and 30 days (T2) after CAS and 2 months after thienopyridine discontinuation (T3). Platelet activation markers (PAC1, CD62 and Tissue Factor [TF] and the percentage of monocyte-platelet aggregates [MPA]) were assessed by whole blood flow cytometry in resting conditions and upon in vitro ADP stimulation and reported as %UR. As a comparison, platelet activation in 16 healthy subjects was also analyzed (Controls). Results . In resting conditions, CD62 and PAC1 positive platelets and MPA were constant throughout the time points examined (average T0-T3: 0.22±0.02, 0.16±0.01, 9.51±0.68 respectively) and similar to those found in Controls. In vitro ADP-induced CD62, PAC1 and MPA levels were significantly higher at T3 when thienopyridine was discontinued compared to T0, T1 and T2 and similar to that observed in Controls. Levels of TF positive platelets were constant, in resting conditions, throughout the time points examined (average T0-T3: 5.04±0.43), but 3 fold higher that those found in Controls (1.95±0.56, p&lt;0.01). Drug treatment does not inhibit ADP-induced TF expression being the values similar to those found in Controls. Conclusions . Significant higher levels, compared to Controls, of TF-positive platelets circulating in peripheral blood of CAS patients. Dual antiplatelet therapy inhibits the expression of all ADP-induced platelet activation markers, but TF. This prothrombotic platelet phenotype may have implications for CAS complications.
Abstract 5537: Inhibition of Pancreatic Lipase and the Renin Angiotensin System Synergistically Decreases Body Fat
Authors: Feng Li, Nobuyuki Takahashi
Journal: Circulation (2009)

We have recently demonstrated that mice lacking renin are lean, and excrete more fat in the feces, which is associated with less than 20 % expression of pancreatic lipase and colipase. Treating wild type (WT) mice with an angiotensin receptor blocker losartan (ARB) or an angiotensin converting enzyme (ACE) inhibitor enalapril does not affect body weight, body fat, fecal fat excretion and pancreatic lipase expression, although their colipase expression in the pancreas is decreased to the low levels of the Ren1c −/− mice. Because colipase is necessary for activation of lipase, we hypothesized that inhibition of both pancreatic lipase and colipase by combination of ARB or ACE inhibitor and lipase inhibitor (orlistat) more effectively decreases body weight and body fat than either of them alone. Treating WT mice with both losartan (0.45g/L in drinking water) and orlistat (200 mg/kg diet) for two weeks reduced the body fat significantly more than mice treated with losartan alone or orlistat alone (control 12.5±1.42 %, losartan 8.7±1.9 %, orlistat 3.8±0.8 %, losartan + orlistat 0.2±2.5 %). The fecal fat content in mice treated with losartan and orlistat is also significantly higher than that of mice treated with losartan alone or orlistat alone (control 46.1±6.2 mg/day, losartan 32.0±4.0 mg/day, orlistat 137.1±9.6 mg/day, losartan + orlistat 186.0±39.6 mg/day). We conclude that inhibiting pancreatic lipase and colipase by using combination of lipase inhibitor and ARB or ACE inhibitor is a promising treatment of the metabolic syndrome. This research has received full or partial funding support from the American Heart Association, Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia &amp; Washington, DC).
Abstract 5619: Bleeding With Clopidogrel Plus Aspirin in Stroke Prevention in Atrial Fibrillation Compared to Bleeding With Warfarin: Lessons From ACTIVE-W and ACTIVE-A
Authors: Freek W Verheugt, Jeroen Jaspers Focks, Marc A Brouwer
Journal: Circulation (2009)

Rationale : Many patients with atrial fibrillation (AF) are felt ineligible for warfarin often due to a perceived unacceptable bleeding risk. Aspirin was shown to be an inferior alternative. In warfarin eligible patients in the large ACTIVE-W study stroke prevention with aspirin plus clopidogrel (A+C) was inferior to warfarin, whereas bleeding with A+C was unexpectedly quite similar to that of warfarin. Recently, in patients ineligible for warfarin in the large ACTIVE-A trial A+C was found to be superior to aspirin alone against stroke, but at the cost of a significantly increased risk of bleeding including hemorrhagic stroke. Here we put both trials into perspective with regard to safety, efficacy and trade-off. Methods : In ACTIVE-W patients eligible for warfarin (n=6,706) were randomized to warfarin or A+C and followed for 1.8 year (y) when the trial was stopped prematurely. Patients ineligible for warfarin (n=7,554) were randomized in ACTIVE-A to A+C or aspirin alone and followed for 3.6 y. Clopidogrel dose was 75 mg and aspirin dose 75–100 mg daily in both trials. Results: Baseline risk was highly comparable in both ACTIVE-trials (table ). Conclusions : The lowest stroke rate is seen with warfarin. Major bleeding with A+C is rather similar in both trials and comparable with warfarin. Given the bleeding with A+C in both warfarin eligible and ineligible patients, warfarin has the most favorable trade-off. These results suggest that perceived bleeding risk per se does not make AF patients ineligible for warfarin. Thus, warfarin should remain the cornerstone for stroke prevention in AF.
Abstract 5530: Associations Between Arterial Blood Pressure and Adipokines Expression in Subcutaneous, Femoral and Pericardial Adipose Tissue in Patients With Coronary Atherosclerosis
Authors: Constantinos Bakogiannis, Charalambos Antoniades, Dimitris Tousoulis, Alexis S Antonopoulos, Evangelia Ntalarizou, Antigoni Miliou, Costas Psarros, Costas Triantafyllou, Dimitris Lymperiadis, Christodoulos Stefanadis
Journal: Circulation (2009)

Background: Adipokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and adiponectin are synthesized in adipose tissue (AT) and may affect the development of hypertension. We characterised the synthesis of these adipokines in subcutaneous, femoral and pericardial AT of patients with advanced atherosclerosis, and we examined their impact on arterial blood pressure. Methods: Fifty patients undergoing elective CABG (14 hypertensives 36 non-hypertensives) were recruited. Subcutaneous AT was collected from the site of CABG incision, femoral AT was collected from the area surrounding the saphenous vein (perivascular) and pericardial AT was collected from the site close to the right ventricle. AT was transferred to the lab within 30 minutes and was cultured ex-vivo for 4 hours. MCP-1, IL-6 and adiponectin were quantified in AT culture supernatants. Results: Hypertension was associated with higher IL-6 in pericardial adipose tissue (14.7±1.8 vs 10.0±1.5 pg/mg p&lt;0.05), MCP-1 (7.07±1.2 vs 2.7±0.6 pg/mg p&lt;0.05) and adiponectin (229.5±15.9 vs 168.9±19.3 pg/mg, p&lt;0.05). Importantly, hypertension was not associated with femoral IL-6 (10.9±1.3 vs 11.9±2.2 pg/mg p=NS), subcutaneous IL-6, (6.9±1.0 vs 8.4±2.1 pg/mg p=NS), femoral MCP-1 (5.7±0.8 vs 4.0±1.1 p=NS), femoral adiponectin (174±34 vs 221±26pg/mg p=NS), subcutaneous MCP-1 (2.37±0.29 vs 3.3±1.5 pg/mg p=NS) or subcutaneous adiponectin (175±18 vs 182±23.2 pg/mg p=NS) AT synthesis. Diastolic (but not systolic) blood pressure was strongly correlated with IL-6 in femoral (rho=0.492, p=0.038) and subcutaneous (rho=0.659, p=0.04) but not pericardial (rho=0.386, p=NS) AT. Conclusions: Adipokines (IL-6, MCP-1 and adiponectin) synthesized in pericardial adipose tissue are closely associated with the presence of arterial hypertension in patients with advanced atherosclerosis. However, adipokines synthesised in femoral and subcutaneous adipose tissue are strongly associated with the variability of diastolic but not systolic blood pressure.
Abstract 5570: TRAF5 Deficiency Accelerates Atherogenesis in Mice: A Role for TRAF5 as Protective Factor in Atherosclerosis?
Authors: Anna Missiou, Nerea Varo, Philipp Rudolf, Christian Münkel, Sandra Ernst, Carina Walter, Christoph Bode, Peter Libby, Andreas Zirlik
Journal: Circulation (2009)

Background: TNF receptor associated factors (TRAFs) function as cytoplasmic adaptor proteins for cytokines of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFalpha, and IL-1beta, established mediators of atherogenesis. We recently reported over-expression of TRAFs in atheromata, TRAF-dependent inflammatory gene expression in atheromata-associated cell types, and limitation of atherogenesis in mice deficient for TRAF1. Here, we test the hypothesis that TRAF5 modulates atherogenesis in vivo. Methods and Results: TRAF5–/LDLR– mice consuming a high cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions compared with LDLR– controls. Intimal lesion size increased by up to 328±11% and 174±15% in sections of the aortic arch and aortic root, respectively (n&gt;13 per group, P&lt;0.01 each). Plaques of TRAF5-deficient animals contained up to 149±15% more lipids (P&lt;0.05) and tended to contain more macrophages and less collagen, characteristics associated with vulnerable plaques in humans. Smooth muscle cell content and lymphocyte content remained unchanged. In vitro, TRAF5-deficient endothelial cells expressed higher levels of the adhesion molecule VCAM-1 and the chemokine KC. Furthermore, TRAF5-deficient macrophages took up increased amounts of acethylated LDL (N=3). Finally, patients suffering from stable coronary heart disease and acute coronary syndrome expressed significantly lower amounts of TRAF5 mRNA in blood than healthy controls (0.026±0.0016 vs. 0.023±0.0018 vs. 0.029±0.0017 TRAF5/GAPDH mRNA, N=325, P&lt;0.01) supporting a protective role of TRAF-5 in atherosclerosis. Conclusions: We present the novel finding that TRAF5 deficiency accelerates atherogenesis in mice. These data identify TRAF5 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.