tbuckley/cabot-search huggingface dataset:
Abstract 4941: Dietary Alpha-Linolenic Acid Supplementation Inhibits Thrombus Formation in vivo
Authors: Erik HOLY, Jürg H Beer, Marc Forestier, Alexander Akhmedov, Pavani Mocharla, Thomas F Luscher, Felix C Tanner
Journal: Circulation (2009)

Background. Considering the reduced availability of marine derived long-chain n-3 fatty acids (n-3 FA), the use of the plant-derived n-3 FA α -linolenic acid (ALA) may constitute an attractive cardioprotective alternative. However, despite promising epidemiological data, the effect of dietary ALA supplementation on arterial thrombus formation remains unknown. Methods and Results. 8 week-old male C57Bl/6 mice were fed either a high ALA (7.3g%) or low ALA (0.03g%) diet for 2 weeks. Mice fed a high ALA diet showed delayed carotid artery thrombus formation in a mouse photochemical injury model as compared to mice on a low ALA diet (68±6 vs 40±4.2 minutes; n=7; p&lt;0.05). High dietary ALA supplementation impaired platelet aggregation as determined by whole blood aggregometry in isolated murine platelets (n=5; p&lt;0.005), without affecting PTT and aPTT clotting times (n=7; p=NS). Mice on the high ALA diet exhibited reduced vascular tissue factor (TF) expression and activity, as well as reduced vascular NF kappa B activity (n=7; p&lt;0.05). In human endothelial, vascular smooth muscle, and peripheral blood mononuclear cells ALA (10 –30 μ mol/l) inhibited tumor necrosis factor (TNF)- α and thrombin induced TF expression as well as surface activity (n=4; p&lt;0.01). Real time PCR and analysis of TF promoter activation demonstrated that ALA mediated inhibition of endothelial TF expression occurred at the transcriptional level involving the MAP kinases p38, ERK and JNK1/2 (−62%,−55% and −28% versus TNF- α alone; n=3; p&lt;0.05). In endothelial cells ALA impaired TNF-á induced I kappa B-á degradation and NF kappa B activation (n=3; p&lt;0.05). Conclusions. A diet rich in plant-derived ALA inhibits arterial thrombus formation via impaired platelet aggregation and reduced TF expression. Hence, dietary ALA supplementation represents an attractive antithrombotic nutritional supplement.
Abstract 4952: Transplant Vasculopathy Response in CCR2 and NDST-1 Deficient Mice Aortic Transplant Model After Viral Anti-Inflammatory Chemokine Modulating Protein, M-T7, Treatment
Authors: Mr Erbin Dai, Mrs Liying Liu, Mrs Mee Bartee, Ms Dana McIvor, Mr Yun ming Sun, Mr Colin Macaulay, Mr Jeffrey D Esko, Mr Israel Charo, Mrs Alexandra R Lucas
Journal: Circulation (2009)

Background: Transplant vasculopathy impedes long-term organ transplant survival. Chemokines direct inflammatory cell migration, through binding to glycosaminoglycans (GAGs) on the surface of endothelial cells and in connective tissues. Chemokines bind GAGs via the C terminus and receptors via the N terminus. Both chemokine receptor and chemokine GAG interactions are important to inflammatory responses. Chemokines and chemokine receptors have been demonstrated to have important roles in transplant rejection. The relative roles of receptor and GAG interaction in transplant vasculopathy are not defined. Myxoma viral chemokine modulating protein (CMP) M-T7 interrupts C terminal GAG binding of C, CC and CXC chemokines. In prior work M-T7 reduced transplant vasculopathy in aortic and renal transplant models. We examine here the effects of CCR2 and GAG deficiency as well as M-T7 treatment in CCR2 and heparan sulfate (HS-GAG) deficient mouse aortic allograft transplant models. Methods: CCR2 −/− or CCR2 +/+ donor Balb/C aorta was transplanted to C57BL/6 recipients HS-GAG +/+ and HS-GAG −/− aorta was transplanted to Balb/C. WT to CCR2 −/− or NDST-1 −/− reverse aortic transplant was also examined. All aortic transplant group were assessed with and without M-T7 treatment. Plaque growth and macrophage/T cell invasion were measured at 28 days. Results: Plaque growth was significantly decreased in both CCR2 −/− and HS-GAG −/− transplants when compared to CCR2 +/+ (P = .021) or HS-GAG +/+ (P = .032), respectively. Immunostaining demonstrated reduced CD3 T-cell and macrophage invasion. Plaque was reduced in WT HS-GAG +/+ when compared to WT Balb/C aortic transplant (P = .306). Reverse Transplant of WT C57Bl/6 or Balb/C donor aorta to CCR2 −/− or HS-GAG −/− mice, respectively, did not reduce plaque growth. M-T7 treatment reduced plaque growth in both CCR2 +/+ (P &lt; .047) and CCR2 −/− (P = .017) aortic transplant, but had reduced inhibitory activity in HS-GAG −/− aortic transplants when compared to HS-GAG +/+ . Conclusion: Heparan sulfate GAG is an important mediator in transplant vasculopathy development. Interruption of chemokine: GAG binding provides a new therapeutic target for prevention of transplant vasculopathy.
Abstract 4950: Loss of SM22 Couples Arterial Inflammation With Osteochondrogenesis in a Murine Artery Injury Model
Authors: Jianbin Shen, Maozhou Yang, Donghong Ju, Hong Jiang, Jianpu Zheng, Li Li
Journal: Circulation (2009)

Expression of vascular smooth muscle cell (VSMC) cytoskeleton markers including SM22 is down-regulated in arterial diseases including atherosclerosis where inflammation and calcification are present. However, the role of this down-regulation in arterial pathogenesis is unknown. Hypothesis : Down-regulation of SM22 may actively contribute to arterial pathogenesis. Methods : Five Sm22 knockout ( Sm22 −/− ) mice and their wild type littermates were subjected to carotid denudation, an artery injury model. Analyses were conducted on carotids two weeks after injury. SM22 knockdown was performed in triplicate using siRNA in a VSMC line, PAC1, followed by downstream experiments 3 days after transfection. Results : Sm22 −/− mice developed both enhanced arterial inflammatory response and prominent medial osteochondrogenesis along with remarkable NF- κ B activation compared to their wild-type littermates. The inflammation was evidenced by excessive artery swelling, macrophage infiltration and high induction of pro-inflammatory molecules including COX-2, MCP-1, VCAM-1, ICAM-1 and CX3CL1. The medial osteochondrogenesis was characterized by augmented expression of type II collagen, aggrecan, osteopontin, BMP2, SOX9 and RUNX2. In accordance with the in vivo findings, expression of the aforementioned pro-inflammatory genes and two key osteochondrogenic transcription factors Sox9 and Runx2 was up-regulated after SM22 knockdown in PAC1 cells. Interestingly, SM22 knockdown also led to NF- κ B activation, and inhibition of NF- κ B pathway reversed the up-regulation of both pro-inflammatory genes and osteochondrogenic genes. As an initiator of NF- κ B activation, reactive oxygen species (ROS) production was boosted after SM22 knockdown, and ROS scavenging effectively blocked NF- κ B activation and induction of these genes. Further, the compromised actin cytoskeleton after SM22 knockdown might contribute to the elevated ROS. Conclusions : These findings suggest that loss of SM22 in VSMCs coupled injury induced arterial inflammation with osteochondrogenesis in part via ROS induced NF- κ B activation and that SM22 plays both anti-inflammatory and anti-osteochondrogenic roles in arterial diseases partly by maintaining actin cytoskeleton integrity.
Abstract 610: The Pig Heart Harbors Cardiac Stem-Progenitor Cells which Respond to Increasing Growth Factor Stimulation Regenerating the Infarcted Myocardium
Authors: Georgina M Ellison, Daniele Torella, Ioannis Karakikes, Alejandro Diego Nieto, Fellipe Fernandez, Claudia Perez-Martinez, Armando Perez, Bernardo Nadal-Ginard
Journal: Circulation (2006)

Recent reports on murine models have raised the possibility of regenerating contractile myocardial tissue by in situ activation and mobilization of cardiac stem/progenitor cell (CSC) by growth factors (GF). Extrapolation of murine results to the human are doubtful because the human requires ~ 5x10 3 larger regenerated mass. We sought to establish the effects of CSC in situ mobilization by intracoronary injections of IGF-1 and HGF after MI in pigs. To this aim, in 23 female Yorkshire pigs, a 75 min PTCA LAD occlusion was used to induce acute MI. Five hours later, IGF-1 and HGF were administered to 16 instrumented pigs. Total doses of GF ranged from 200 to 800ng/ml. Saline was injected in the other 7 pigs with MI. Three pigs received a second dose of GFs at 14 days. All pigs were sacrificed at 28 days after MI and GF administration. To track myocardial regeneration, BrdU was administered via osmotic pumps. Cardiac function was measured by echocardiography and LV catheterization. Cardiac tissue from sham operated pigs was collected and CSCs extracted for in vitro analyses. These CSCs displayed stem cell properties of clonogenicity, self-renewal and multipotency similar to rodent CSCs. Moreover, they expressed functional IGF-1R and c-met receptors. The GF-treated infarcted heart showed a significant increase in the number of c-kit pos CSCs in the border of the infarct and even higher in the ischemic area. Most of these CSCs were BrdU pos /Ki-67 pos . Many c-kit pos cells expressed the transcription factors, MEF-2C, Ets-1 and GATA6 indicative of myocyte, endothelial cell and smooth muscle differentiation, respectively. Interestingly, the infarcted area was substantially replaced by new myocardium in direct correlation to the amount of GF administered. These hearts had a significant and increasing number of small BrdU pos (up to 14±3%) and Ki-67 pos (up to 12±2%) myocytes. Moreover, newly formed vascular structures were evident in the infarcted myocardium. Myocardial regeneration was absent in untreated pigs. Importantly, LV function was significantly improved in GF treated, compared to controls. Therefore, it is possible and practical to produce effective myocardial regeneration post-MI in hearts the size of the human’s following intracoronary injection of GFs.
Abstract 4840: Are Statins Nephroprotective? A PCI Study to Explore for Possible Pleiotropism
Authors: Valentyna Ivanova, Jennifer Spotti, David M Lasorda, Diane A Vido, Saundra B Grant, Robert W Biederman
Journal: Circulation (2009)

HMG-CoA reductase inhibitors (statins) are used for dyslipidemia treatment and CAD prevention. Considerable controversy exists regarding statins’ possible pleiotropic effect with many vascular and nonvascular beds benefiting from their use. However, little data exists to support possible nephroprotective statins effect or their potential for ‘nephro-pleiotropism’. Hypothesis We hypothesize that pre-administration of statins in patients prior to undergoing percutaneous coronary intervention (PCI) may be beneficial in preventing contrast induced nephropathy (CIN) due to a pleiotropic effect. Methods A retrospective study of &gt;4000 patient charts who underwent PCI for routine clinical reasons was performed. Pts who developed CIN were selected based on serum creatinine (SCr) level elevation by ≥0.5mg/dL from baseline and further stratified into statin use (+/−) prior to PCI and by LDL level. Results SCr was measured within 1 week prior to or on day of PCI in 805 pts: 516 (64%) male, 289 (36%) female and within 1 week post PCI. Statin therapy was initiated in 328 (41%) pts ≥1 week prior to PCI. When classified by statin use (+/−), there was no difference in incidence of CIN (29 vs 39, p=0.8). However, there was a significant number of pts with SCr rise to &gt;2.5mg/dL in the statin(−) group (p&lt;0.05). When limited to absolute rise in SCr, the mean rise in SCr was 0.64 in statin(−) vs 0.16mg/dL in statin(+) subgroup, representing a 3-fold nephroprotective effect of statins (p&lt;0.001). Via multivariate analysis, neither age, gender, HTN, DM or contrast load was a significant predictor for the rise in SCr. In 44 pts (16 statin(+), 28 statin(−)) with recent LDL levels there was no difference in the mean LDL (99 vs 91mg/dL respectively, p=NS) and this pattern held true when categorized by LDL &lt;70, &lt;100, or &lt;130mg/dL (p=NS for all), again independent of all defined comorbidities. Conclusions Pre-PCI administration of statins is strongly nephroprotective. Multivariate analysis demonstrates the 3-fold nephroprotection is independent of common clinical high risk comorbidities. A more controversial finding implicates the lack of a direct anti-atherosclerotic LDL lowering effect as the genesis since LDL levels were nearly superimposable, implying substantial pleiotropism.
Abstract 4922: Epoprostenol Induces Apoptosis By Inhibiting The Expression Of Survivin In Pulmonary Artery Smooth Muscle Cells
Authors: Satoshi Akagi, Kazufumi Nakamura, Kengo Kusano, Hiromi Matsubara, Hiroshi Ito
Journal: Circulation (2009)

Background: Pulmonary arterial hypertension (PAH) is associated with suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Survivin has been reported to suppress caspase activities and plays an important role in the mechanism of suppressed apoptosis. In this study, we investigated whether epoprostenol exerts the pro-apoptotic effects by inhibiting the expression of survivin in PASMCs. Methods: We studied the induction of apoptosis by epoprostenol in PAH-PASMCs (n = 5) and non-PAH-PASMCs (n = 3). We investigated the expression of survivin in lung tissues obtain from 5 idiopathic PAH patients and 3 non-PAH patients, and in PAH-PASMCs and non-PAH-PASMCs by immunocytochemical analysis. We examined the protein level of survivin in PAH-PASMCs treated with epoprostenol or diluents by western blotting. We also examined the time course of mRNA level of survivin treated with epoprostenol or diluents by quantitative RT-PCR. Results: TUNEL-positive cells, caspase-3- and -7-active cells, condensation of chromatin along the nuclear membrane, and fragmentation of the nucleus were found in PAH-PASMCs treated with epoprostenol. Epoprostenol significantly induced apoptosis in PAH-PASMCs compared with that in non-PAH-PASMCs (5.64 ± 0.82% versus 0.64 ± 0.25%; P &lt; 0.05). Survivin was expressed in lung tissues obtained from idiopathic PAH patients but not from non-PAH patients. Survivin was also expressed in PAH-PASMCs but not non-PAH-PASMCs with immunocytochemical analysis. Treatment with epoprostenol for 24 hours significantly suppressed the protein level of survivin by 52% compared with treatment with diluents in PAH-PASMCs (P &lt; 0.05). Epoprostenol significantly decreased the mRNA level of survivin after 12 hours (29%; P &lt; 0.05) and 24 hours (10%; P &lt; 0.05) treatment compared with diluents. Conclusions: Epoprostenol can induce the apoptosis by inhibiting the expression of survivin in PAH-PASMCs.
Abstract 4174: The Association of Coffee Consumption With Wave Reflections in Hypertensive Patients
Authors: Charalambos Vlachopoulos, Nikolaos Alexopoulos, Gregory Vyssoulis, Panagiota Pietri, Alexandra Zervoudaki, Konstantinos Aznaouridis, Konstantina Aggeli, Christodoulos Stefanadis
Journal: Circulation (2006)

Introduction: Wave reflections are important markers and prognosticators of cardiovascular risk, and have been implicated in the pathogenesis of systolic hypertension. Caffeine increases acutely wave reflections. Furthermore, chronic coffee consumption is associated with increased wave reflections in normotensive subjects. Hypothesis: In the present study we aimed to assess the association between chronic coffee consumption and wave reflections in hypertensive patients. Methods: We examined 228 never treated hypertensives (age 50.7±11.9 years, 143 males) under no medication. Frequency of coffee consumption was assessed using a validated food frequency questionnaire. According to the distribution of coffee consumption, we categorized daily coffee consumption as: none low (&lt;200 ml/day) moderate (200 – 450 ml/day) and high (&gt;450 ml/day). Augmentation Index (AIx) was measured non-invasively as an index of wave reflections, using SphygmoCor®. Analysis of covariance (ANCOVA) was applied to evaluate the association between AIx and coffee intake after adjusting for several potential confounders. Results: AIx was found to be increased with increasing degree of daily coffee consumption when adjusted for gender, age, height, smoking status, heart rate, mean pressure, HDL cholesterol and hsCRP (p&lt;0.02, Figure ). Systolic, diastolic, pulse and mean pressures were not different among the 4 groups of daily coffee consumption. Conclusions: Increased daily coffee consumption is associated with enhanced wave reflections in hypertensive patients. This finding may have important implications for the management of these patients.
Abstract 596: Cardiac Autophagy is a Maladaptive Response to Hemodynamic Stress
Authors: Hongxin Zhu, Paul Tannous, Janet L Johnstone, Yongli Kong, John M Shelton, James A Richardson, Beth Levine, Beverly A Rothermel, Joseph A Hill, Donald W Reynolds
Journal: Circulation (2006)

Background: Autophagy is a highly conserved mechanism of protein and organelle degradation linked to several neurodegenerative diseases. Nothing is known about the possible role of autophagy in heart failure. Methods and Results: Short-term nutrient deprivation, an established trigger of autophagy, induced dramatic increases in the ratio of LC3-II:LC3-I in ventricular lysates, indicative of increased autophagic activity. To determine the specific contribution of cardiomyocyte autophagy, we generated αMHC-GFP-LC3 transgenic mice. Short-term starvation induced a robust increase in the punctate localization of GFP-LC3 in myocytes, demonstrating cardiomyocyte autophagy and confirming the validity of our “autophagy reporter” mice. To test for autophagy in failing heart, we induced pressure overload by severe constriction of the thoracic aorta (sTAB). Fluorescence microscopy demonstrated autophagosome-localized GFP-LC3 in left ventricular myocytes 24h after banding which peaked at 48h and subsequently declined (though remaining elevated relative to control, p&lt;0.05). EM revealed double-membrane autophagosomes in cardiomyocytes in failing heart. Lysosome activity was increased in failing LV as demonstrated by immunostaining for cathepsin D and LAMP-1, suggesting that diminished activity of distal lysosomal pathways was not responsible for autophagosome accumulation. To explore whether cardiomyocyte autophagy is beneficial or maladaptive, we studied mice with targeted disruption of beclin 1 , a gene required for autophagosome formation. Heterozygous disruption of beclin 1 led to decreased autophagy in pressure-stressed cardiomyocytes. Heart failure-associated declines in LV systolic function were significantly attenuated in beclin 1 mutants. Beclin 1 over-expressing transgenic mice manifested an amplified pathological response to sTAB. Compared with WT, beclin 1 transgenic mice subjected to standard TAB manifested increased autophagic activity, impaired systolic performance, increased load-induced fibrosis, but similar levels of apoptosis. Conclusions: These findings implicate autophagy in the pathogenesis of load-induced heart failure and suggest it may be a target for novel therapeutic intervention.
Abstract 4202: Migraine is Associated with Increased Risk of Cardiovascular Disease in Men
Authors: Tobias Kurth, J. Michael Gaziano, Nancy R Cook, Vadim Bubew, Giancarlo Logroscino, Hans-Christoph Diener, Julie E Buring
Journal: Circulation (2006)

Background: The vascular component of the migraine-specific physiology and an observed adverse cardiovascular risk profile among migraineurs suggest an association between migraine and cardiovascular disease (CVD). In women, migraine has recently been associated with increased risk of CVD, including coronary events. Compatible data in men are lacking. Objectives: To evaluate the association between migraine and subsequent CVD as well as specific CVD events in apparently healthy men. Methods: Prospective cohort study among 20,084 men participating in the Physicians’ Health Study. In yearly questionnaires, men were asked for information on migraine, risk factors, and the occurrence of study endpoints. We classified men as having migraine if they indicated migraine during the first 60 months, after which follow-up began. Information on aura was not available. All men were free of outcome events at start of follow-up. During 15.7 years, we followed participants for the occurrence of a first major CVD event (nonfatal ischemic stroke, nonfatal myocardial infarction, or death from ischemic CVD). We also evaluated the individual endpoints as well as coronary revascularization and angina. Results: A total of 1449 (7.2%) men reported migraine and during follow-up 2236 major CVD events occurred. Compared to non-migraineurs, men who reported migraine had multivariable-adjusted hazard ratios (95% confidence intervals) of 1.24 (1.06–1.46; P=0.008) for major CVD, 1.12 (0.84–1.50; P=0.43) for ischemic stroke, 1.42 (1.15–1.77; P&lt;0.001) for myocardial infarction, 1.05 (0.89–1.24; P=0.54) for coronary revascularization, 1.15 (0.99–1.33; P=0.068) for angina, and 1.07 (0.80–1.43; P=0.65) for ischemic cardiovascular death. Conclusions: In this large prospective cohort of apparently healthy men, migraine was associated with increased risk of major CVD, which was driven by the increased risk of myocardial infarction.
Abstract 5051: GATA-4 Promotes Mesenchymal Stem Cells Transdifferentiation Into Cardiomyocyte via Insulin Growth Factor Binding Protein 4 Upregulation
Authors: Hongxia Li, Shi Zuo, Zhisong He, Yigang Wang, Muhammad Ashraf, Meifeng Xu
Journal: Circulation (2009)

It has been reported that GATA-4 stimulates differentiation of beating cardiomyocytes from stem cell. However, the underlying mechanism remains unknown. We hypothesize that GATA-4 enhances MSC mediated myogenesis via upregulating insulin growth factor binding protein 4 (IGFBP-4). Method: MSC were isolated from rat bone marrow and transfected with GATA-4 (MSC GATA-4 ) using Clontech pMSCV retroviral expression system. MSC transfected with GFP (MSC GFP ) was used as control. Cardiomyocytes (CM) were obtained from neonatal rat ventricles. The transdifferentiation of MSC was directly studied by co-culture MSC with CM, and confirmed by immunostaining and quantitative PCR. Results: GATA-4 not only remarkably upregulated the expression of myogenic genes (Table ), but also significantly increased the expression of IGFBP-4 (9.21±0.60 fold in MSC GATA-4 ) compared to those in MSC GFP . After co-culture with CM for 7 days, some MSC were tested positive for α -actinin (Fig. A ). The percentage of α -actinin positive green cells was significantly higher in MSC GATA-4 (34.9%) than that in MSC GFP (8.6%). The expression of cardiac markers, including BNP, Nkx2.5 and Islet-1 was significantly increased in MSC GATA-4 (Fig. B ). Transdifferentiated MSC also showed action potential which was similar to the native CM. To determine whether IGFBP-4 enhanced MSC mediated myogenesis, IGFBP-4 neutralizing antibody (20~40 μ g/ml) was added into culture medium, which attenuated MSC GATA-4 differentiatiation into cardiomyocyte. Conclusion: GATA-4 promotes MSC differentiation into myocardial phenotypes partially via upregulating IGFBP-4. Table 1. The expression of cardiac genes in MSC GATA-4 (microarray analysis)