tbuckley/cabot-search huggingface dataset:
Abstract 5488: Comparison of Primary With Fibrinolytic-based Facilitated PCI and Comparison of Fibrinolytic-based PCI With Fibrinolysis Followed by Standard Care for STEMI: Updated Quantitative Review of Randomized Trials
Authors: Holger Thiele, Ingo Eitel, Steffen Desch, Gerhard Schuler
Journal: Circulation (2009)

Background: Facilitated PCI for STEMI is defined as the use of pharmacological substances before a planned immediate intervention (&lt; 3h), to improve coronary patency. We undertook an updated meta-analysis of randomized controlled trials to compare fibrinolytic-based facilitated and primary PCI and fibrinolytic-based facilitated PCI and fibrinolysis followed by standard care. Methods: We identified 12 trials of patients with STEMI assigned to facilitated (n=2498) or primary (n=2488) PCI and 8 trials with comparison facilitated PCI (n=969) vs fibrinolysis with standard care (n=955). Outcomes of death, stroke, non-fatal reinfarction, urgent TVR, and major bleeding were assessed. Results: The facilitated approach resulted in a greater than two-fold increase in the number of patients with initial TIMI-3-flow compared with primary PCI approach (p&lt;0.001); however, final rates did not differ (p=n.s.). Significantly more patients assigned to facilitated PCI than those assigned to primary PCI died (5.3% vs 3.9%; RR 1.36; 95% CI 1.04; 1.77; p=0.02), had higher non-fatal reinfarction rates (3.3% vs 1.7%; RR 1.99; 95% CI 1.36; 2.92; p&lt;0.001), higher urgent TVR rates (3.3% vs 1.3%; RR 2.48; 95% CI 1.57; 3.97; p&lt;0.001), and higher stroke rates (1.3% vs 0.5%; RR 2.76; 95% CI 1.38; 5.64; p=0.002). Facilitated PCI was also associated with higher rates of major bleeding (6.4% vs 3.9%; RR 1.62 95% CI 1.26; 2.09; p&lt;0.001). In the 2nd comparison, facilitated PCI did not result in a mortality difference (5.1% vs 5.7%; RR 0.89; 95% CI 0.60; 1.33; p=0.63) and no difference in non-fatal reinfarction (4.2% vs 5.2%; RR 0.81; 95% CI 0.52; 1.25; p=0.37). However, there was a difference in non-fatal reinfarction in the stenting era (4.0% vs 7.0%; RR 0.57; 95% CI 0.34; 0.95; p=0.03). There was no difference in major bleeding and stroke in the comparison of facilitated PCI vs fibrinolysis with standard care. Conclusions: Fibrinolytic-based facilitated PCI has substantial harm in comparison to primary PCI. In comparison to fibrinolysis with standard care facilitated PCI leads to a small reduction in reinfarction but has no beneficial effect on mortality. A strategy of primary PCI should therefore be implemented for all STEMI patients.
Abstract 5500: <i>PDGFD</i> Variation is Associated With Increased Susceptibility to First-ever Non-hypertensive Intracerebral Hemorrhage Whereas Predicts Decreased Risk of Recurrence
Authors: Yongyi Bai, Jingzhou Chen, Kai Sun, Yibo Wang, Xiqi Xu, Rutai Hui
Journal: Circulation (2009)

Background Platelet-derived growth factor D (PDGF-D) is a most recently discovered member of the PDGF family and plays an important role in angiogenesis, vessel remodeling and repairing in response to injury. We hypothesized that genetic variation in PDGFD gene might alter the susceptibility to stroke. Methods We determined the genotypes of a single nucleotide polymorphism (SNP) (−858A/C, rs3809021), the only identified tag-SNP in the promoter region of PDGFD from the HapMap CHB sample, in 1484 patients with stroke (654 cerebral thrombosis, 419 lacunar infarction, 411 intracerebral hemorrhage [ICH]) and 1528 control subjects from an unrelated Chinese Han population and followed the stroke patients up for a median of 4.5 years (range 0.1 to 5.4). Functions of −858 variant were studied by using luciferase reporter assays. Results The SNP −858A-bearing PDGFD promoter exhibited 3.78-fold increase of transcription activity than the SNP −858C-bearing promoter. Genotype analyses were conducted for both dominant and additive models. The A allele of the −858 locus showed significantly increased risk of ICH (dominant model: odds ratio [OR] 1.29, 95% confidence interval [CI] 1.00 to 1.68, P =0.05; additive model: OR 1.24, 95% CI 1.01 to 1.52, P =0.04) than wild-type genotype. Further analyses showed that −858 A allele conferred about 2-fold increase in risk of non-hypertensive ICH (dominant model: OR 2.1, 95%CI 1.34 to 3.29, P =0.001; additive model: OR 1.75, 95% CI 1.24 to 2.46, P =0.001). After a median follow-up of 4.5 years, 52 patients had a recurrent ICH. After adjusting for conventional cardiovascular risk factors, we found that −858 A allele was associated with a reduced risk of ICH recurrence (dominant model: adjusted hazard ratio [HR] 0.09, 95%CI 0.01 to 0.74, P=0.025; additive model: HR 0.21, 95% CI 0.04 to 1.16, P =0.073) in non-hypertensive patients. No association was observed between the PDGFD variant and hypertensive ICH and atherothrombotic stroke. Conclusions The −858A allele was associated with increased first-ever non-hypertensive ICH and was a predictor of lower risk of ICH recurrence. Further studies should be conducted to reveal the role of PDGF-D at various stages of ICH development beneficial, or deleterious.
Abstract 5473: TGF <i>β</i> Induction of Vascular Smooth Muscle Differentiation Markers is Mediated by Nox4 and p38 Mitogen-activated Protein Kinase
Authors: Abel Martin-Garrido, David I Brown, Alicia N Lyle, Anna Dikalova, Kathy K Griendling
Journal: Circulation (2009)

Vascular smooth muscle cells (VSMCs) undergo phenotypic transformation in response to environmental cues. In response to injury, VSMC switch from a “contractile” to “synthetic” phenotype, which is implicated in restenosis and arteriosclerosis. Thus, accelerating VSMC redifferentiation may be one way to limit lesion development. TGF β induces differentiation in VSMC; however, the mechanism is incompletely understood. Previous work has implicated Nox4 in differentiation. In this study, we hypothesized that TGF β induces differentiation via Nox4 and p38 mitogen-activated protein kinase (p38) pathways. In VSMCs, treatment with TGF β (2 ng/mL) for 24 hours increases reactive oxygen species (ROS) production (146±15% vs control) and Nox4 protein expression (150±12% vs control), both of which are reduced by transfection with small interfering RNA against Nox4 (siNox4). At 48 hours, TGF β maximally induces the expression of the differentiation markers smooth muscle alpha actin (SMA) and calponin (CNN) and increased incorporation of SMA into stress fibers. This induction is blunted by preincubation with the flavin oxidase inhibitor diphenylene iodonium (DPI) (90±8% inhibition) or by siNox4 (100% inhibition). To investigate the role of p38, we first demonstrate p38 is activated by TGF β at 60 minutes (370±70%) and it is not ROS dependent, because it is not blocked by preincubation with DPI. However, p38 remains activated for up to 24 hours, as measured by continued phosphorylation of its substrates, heat shock protein 27 (650±48%) and the obligatory differentiation transcription factor serum response factor (280±50%). This late activity of p38 is prevented by DPI (68±10% and 57±5% inhibition of HSP27 and SRF). Moreover, the inhibition of p38MAPK partially reverses the upregulation of SMA (60±20% inhibition) and CNN (67%±23 inhibition) by TGF β , and acts in cooperation with Rho kinase (87±10% and 97±1% inhibition of SMA and CNN). Thus, we conclude that Nox4 and p38 are critical regulators of TGFâ-induced differentiation in VSMC, and that Nox4 maintains the activity of p38. These data raise the possibility that Nox4 and p38 are potential targets in the treatment of cardiovascular diseases in which VSMC dedifferentiation plays a pivotal role.
Abstract 5423: Adaptation to Oxygen Deprivation in Human Pluripotent Stem Cells, Endothelial Progenitors, and Endothelial Cells
Authors: Hasan E Abaci, Rachel Truitt, Eli Luong, German Drazer, Sharon Gerecht
Journal: Circulation (2009)

Hypoxia plays an important role during vascular development and regeneration through accumulation of hypoxia-inducible factor 1 alpha (HIF-1alpha) and activation of downstream pathways. We sought to explore the in vitro response of cultures of human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), human endothelial progenitor cells (hEPCs), and human umbilical cord vein endothelial cells (HUVECs) to normoxic and hypoxic oxygen tensions. We first measured cell growth and dissolved O2 (DO) in media of adherent cultures in atmospheric oxygen, physiological oxygen (5% O2) and hypoxic conditions (1% O2). Higher aerobic metabolism was observed in both hESCs and iPSCs cultured in atmospheric oxygen, while hESCs and iPSCs cultured in 5% and 1% O2 had slower or no cell growth, respectively. At each oxygen tension, feeder-free cultured iPSCs were found to consume higher amount of oxygen than feeder-free cultured hESCs. Transport analysis revealed that the oxygen uptake rate (OUR) of hESCs, iPSCs and HUVECs was low as DO availability decreased, whereas the OUR of hEPCs was found to be low only in 1% O2. Next, we examined HIF-1alpha accumulation and the expression of target genes, including VEGF and angiopoietins (angiogenesis), Glut-1 (metabolism), Bnip3 (autophagy) and Bnip3L (apoptosis). Accumulation of HIF-1alpha was detected in all four cell lines cultured in 1% O2. Corresponding upregulation of VEGF, ANGPT2 and GLUT-1 was observed in response to HIF-1alpha accumulation, while upregulation of ANGPT1 was detected only in hESCs. Upregulation of BNIP3 and BNIP3L was detected in hESCs after being cultured for five hours in 5% and 1% O2, which levels corresponded to decreased and no cell growth, respectively. Flow cytometric analysis revealed changes in cell cycle in response to 5% and 1% oxygen tensions. These results demonstrate different cell responses to physiological and hypoxic environments, recognizing that continuous on-line measurements and control over oxygen environments during SC cultures will make it possible to derive desirable cellular responses.
Abstract 5317: Bone Morphogenetic Protein Recruits a Peroxisome Proliferator-Activated Receptor <i>γ</i> and <i>β</i> -catenin Transcription Factor Complex to Regulate Apelin Expression in Pulmonary Endothelial Cells
Authors: Tero-Pekka Alastalo, Molong Li, Vinicio de Jesus Perez, Hirofumi Sawada, Marlene Rabinovitch
Journal: Circulation (2009)

Our previous studies on the pathobiology of pulmonary arterial hypertension (PAH) demonstrated that bone morphogenetic protein receptor II (BMPRII) mediated signaling plays a key role in pulmonary arterial (PA) endothelial cell (EC) survival and proliferation via activation of beta-catenin ( β C). We have also shown that a β C interacting nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR γ ), is a mediator of BMPRII signaling in PA smooth muscle cells (SMCs). A mouse model with targeted disruption of PPAR γ in EC shows PAH. The downstream gene targets of BMPRII signaling via PPAR γ in EC are, however, unknown. We hypothesized that BMPRII induces a PPAR γ -βC transcription factor complex that regulates genes necessary for PAEC homeostasis. We first performed co-immunoprecipitation (IP) and confocal microscopy to demonstrate a relationship between formation of the PPAR γ -βC complex and EC survival. We identified target genes for PPAR γ - β C complex in PAEC by comparing those on whole genome wide ChIP-Chip analyses with those altered on expression profiling microarrays after silencing either BMPRII or βC by siRNA. PPAR γ - β C complex targets were then analyzed by western immunoblotting and qPCR in PAEC from idiopatic PAH (IPAH) vs. control patients, and in PPAR γ deficient vs. wild type mice. By IP and confocal microscopy we demonstrated that PPAR γ interacts, and co-localizes in the nucleus, with β C in PAEC. This interaction was increased 3 fold upon BMP2 stimulation. Furthermore, ChIP-Chip analysis revealed β C co-occupancy in over 70% of PPAR γ bound promoters. Microarray analyses confirmed significant changes in the expression of 35 of those genes after silencing of BMPRII and β C in PAEC. We then focused on apelin as a ChIP-Chip identified target important in endothelial homeostasis. Loss-of either BMPRII or β C down-regulated apelin &gt; 1.5 fold, and apelin mRNA and protein were decreased in PAEC of IPAH vs. control patients (60% and 35% respectively) and in PPAR γ deficient vs. WT mice (P &lt; 0.05 for all). We conclude that BMP signaling induces a PPAR γ - β C interaction that promotes EC homeostasis by regulating critical targets such as apelin. We speculate that down-regulation of apelin may be important in the pathobiology of PAH.
Abstract 5316: The Regulating Role of MicroRNAs for Smooth Muscle Cell Function
Authors: Wiebke Bielenberg, Andre Prock, Harald Tillmanns, Daniel Sedding
Journal: Circulation (2009)

Background: MicroRNAs (miRNAs) comprise key regulators for cellular function. Maturation and expression of miRNAs is tightly controlled by the two processing enzymes Dicer and Drosha. Up to now, the role of miRNAs for vascular smooth muscle cell (VSMC) function and the development of neointimal lesions remains elusive. Methods and Results: Following wire-induced injury of the femoral artery of C57BL/6N mice, Dicer and Drosha mRNA expression was significantly downregulated at day 10 and 21. Microarray analysis of miRNA expression at these time points revealed a significant downregulation of miRNAs implicated to regulate key molecules of the cell cycle maschinery. Indeed, siRNA-mediated knock down of Dicer or Drosha in human coronary SMC significantly augmented the growth factor-induced expression of CDK4, CDK6, SKP2, accelerated cell cycle progression as determined by FACS analysis and increased VSMC proliferation as determined by BrdU incorporation as well as total cell count. Interestingly, knock down of Dicer and Drosha also augmented migration, whereas there was no effect on apoptosis. Since apoptotic (H 2 O 2 ) or inflammatory stimulation had no effect on dicer and Drosha expression, mitogenic stimulation (FCS) resulted in a robust downregulation of Dicer and Drosha expression. In vivo, the knock down of Dicer and Drosha after wire injury led to increased proliferation of neointimal cells, resulting in a significantly enhanced neointima formation. Further in silico analysis revealed similar and phylogenetically well conserved promoter sets in both promoter regions and the FoxO transcription factor FoxO1a was identified as transcriptional regulator of Dicer and Drosha under mitogenic conditions as determined by ChIP-analysis and siRNA-mediated knock down or overexpression of FoxO1a. Conclusion: These data indicate that the key miRNA-processing enzymes Dicer and Drosha are down regulated in neointimal lesions, most likely by mitogenic stimuli via the Foxo transcription factor FoxO1a. Moreover, altered expression of these enzymes and thus of miRNAs seems to regulate VSMC function, especially proliferation and migration, during the development of vascular proliferative diseases.
Abstract 5324: Skeletal Muscle-specific Overexpression of Insulin-like Growth Factor I Suppresses Angiotensin II-induced Oxidative Stress and Prevents Skeletal Muscle Wasting
Authors: Sergiy Sukhanov, Laura Semprun-Prieto, Tadashi Yoshida, Patrick Delafontaine
Journal: Circulation (2009)

Congestive heart failure (CHF) is a leading cause of cardiovascular mortality and morbidity and is associated with elevated circulating levels of angiotensin II (ANG) and muscle wasting (cachexia), which is an important predictor of poor outcome. We have shown that ANG infusion in FVB mice reduces skeletal muscle IGF-1 expression, increases oxidative stress and induces skeletal muscle wasting. We hypothesized that skeletal muscle-specific IGF-1 overexpression would decrease ANG-induced oxidative stress and muscle wasting. Mice overexpressing IGF-1 under control of the skeletal muscle-specific type II myosin light chain promoter (MLC) and control mice (FVB) were infused with 1 ug/kg ANG or vehicle (SHM) and were pair-fed for 7 days. ANG decreased skeletal muscle weight in FVB (ANG/SHM, gastrocnemius: 99.8±3.6/122.3±4.2 mg, P&lt; 0.01; tibialis anterior: 32.0±1.3/41.3±1.3 mg, P&lt; 0.05; quadriceps: 117.6±6.1/160.6±6.7 mg, P&lt; 0.05), but not in MLC. ANG induced a leftward shift in myofiber size distribution and decreased cross-sectional area (CSA) of type I and type II myofibers in FVB (ANG/SHM, gastrocnemius, type I, 443±22/528±28 um2; type II, 620±40/835±44 um2) and this effect was completely inhibited in MLC as detected by immunostaining with isoform-specific antibodies. Oxidative stress was assessed in muscle homogenates using superoxide-sensitive dye L-012. ANG increased superoxides in FVB by 67% (228±25 vs. 149±21 RFU/mg protein, p&lt;0.005) but did not significantly increase superoxides in MLC (376±99 vs. 298±81 RFU/mg protein, p=NS). 250 uM Apocynin (a specific NADPH oxidase inhibitor) suppressed ANG-induced superoxides in FVB (91±5% decrease vs. DMSO control). Analysis of NADPH oxidase subunit expression indicated that ANG upregulated NOX4 mRNA expression in skeletal muscle and this effect was greater in FVB (3.6-fold increase, p&lt;0.05) compared to MLC (2.1-fold increase, p=NS, RT-PCR). Thus, IGF-1 overexpression suppresses oxidative stress and efficiently blocks skeletal muscle wasting, possibly via inhibition of ANG-induced NOX4 upregulation and NADPH oxidase-dependent superoxide formation. IGF-1 inhibition of skeletal muscle NADPH oxidase activity could provide a novel approach for the treatment of cachexia.
Abstract 5303: Tenascin-c Supports Human Blood Platelet Adhesion and Activation Under Both Static and Flow Conditions
Authors: Mathieu Schaff, Catherine Bourdon, Nicolas Receveur, Jean-Pierre Cazenave, Christian Gachet, François Lanza, Pierre Mangin
Journal: Circulation (2009)

Targeting platelet activating components preferentially expressed in atherosclerotic plaques could represent an attractive anti-thrombotic strategy. Tenascin-C (TN-C) is an interesting candidate due to its high level of expression in atherosclerotic plaques while it is absent from healthy vessels. The aim of our study was to evaluate the capacity of TN-C to support platelet adhesion and activation. Under static conditions, washed platelets adhered to purified TN-C (1,923±206 platelets/mm 2 ) as efficiently as to fibrinogen (2,010±100 platelets/mm 2 ), a well characterized platelet adhesive protein. Perfusion of hirudinated blood through TN-C-coated (50 μ g/mL) micro-capillaries under various shear conditions (300 s −1 to 1,500 s −1 ) led to efficient capture of individual platelets which did not form aggregates in contrast to the response on a collagen matrix. Interestingly, the number of adherent platelets to TN-C was 3.7 and 1.8 higher than onto fibrinogen and von Willebrand factor (VWF) coated surfaces, respectively. In addition, video-microscopy analysis showed that the vast majority of attached platelets displayed a stationary behavior onto TN-C (86.9±4,1%) whereas they rolled over a VWF matrix (78.7±2,4%) and rapidly detached from fibrinogen (83.1±3,2%). These results suggest that TN-C has higher adhesive properties than VWF and fibrinogen under flow. Adhesion to TN-C under flow required the GPIb-IX complex and integrins α IIb β 3 and β 1 as shown by inhibition with blocking antibodies and pharmacological inhibitors. Platelets adherent to TN-C under both static and flow conditions, changed their shape and extended filopodia indicating their activation, which was further confirmed by the observation of a sustained intracellular calcium increase. In conclusion, we provide evidence for the ability of TN-C to support platelet adhesion and activation under static and flow conditions indicating a novel putative role in thrombosis. Its presence in atherosclerotic plaques and its implication in platelet recruitment suggest that TN-C could represent a target for anti-thrombotic drugs.
Abstract 5321: Dicer Depletion in Adult Hearts Induces Oxidative Stress, Mitochondrial Dysfunction and Causes Rapid Loss of Cardiac Function
Authors: Sashwati Roy, Jaideep Banerjee, Surya C Gnyawali, Savita Khanna, Chandan K Sen
Journal: Circulation (2009)

Introduction. Dicer, an RNAse III endonuclease, plays a key role in the processing of miRNA into their functional mature form. A number of recent reports point towards a central role of miRNA in cardiac development and function. However, the short-term effects of dicer deficiency on the function of the adult heart and underlying mechanisms remain to be elucidated. Oxidative stress and dysregulated mitochondrial function are known to play a major role in acute cardiac pathologies. Hypothesis . Arrest of miR maturation by heart-specific dicer knock-out in adult animals result in rapid loss of cardiac function caused by mitochondrial dysfunction and oxidative stress. Methods . Mice homozygous for Dicer-floxed alleles (Dicer fl/fl ) and transgenic Myh6-cre/Esr1 mice were crossed to generate double-transgenic (Myh6-cre/Esr1-Dicer fl/fl ) mice. At 8 weeks of age Myh6-cre/Esr1-Dicer fl/fl mice were treated with vehicle or tamoxifen (tam; 20 mg/kg per day) daily ip injections for five consecutive days. To determine the acute functional consequences of Dicer depletion, heart function was determined using gated cardiac MRI and echocardiography. Myocardial miR profiling was performed using a bead array system. Candidate miRs were verified using quantitative PCR. Results . Tam injection for 5 days effectively depleted Dicer protein in myocardium. miRNA array data show significant (p&lt; 0.05, n=3) decrease in the levels of a number of abundant mature miRNA including miR-1, miR-133 a&amp;b. Following 5 days of Tam injection, a significant (p&lt; 0.05, n=5) decrease in ejection fraction (32±9%↓), stroke volume (23±7%↓) and cardiac output (28.3±6%↓) was noted in Dicer −/− compared to Dicer +/+ mice. Studies with isolated mitochondria showed a significant decrease in energy dependent pore opening and increase in uncoupled mitochondria in the heart of Dicer −/− mice. Such compromise in mitochondrial function was associated with structural disintegration and increased (30±7.5%↑; p&lt;0.05, n=3) tissue oxidative stress. Conclusions . This study provides first evidence demonstrating that depletion of dicer in adult mice results in mitochondrial dysfunction and oxidative stress in the myocardium which is followed by acute loss of cardiac functions.