tbuckley/cabot-search huggingface dataset:
Abstract 4191: Abnormal Cardiac Energetics are Associated with Diastolic Dysfunction in Uncomplicated Obesity
Authors: Monique Robinson, Michaela Scheuermann-Freestone, Andrew Blamire, Peter Styles, David Manners, Gillian C Watson, Kieran Clarke, Stefan Neubauer
Journal: Circulation (2006)

Background: Abnormal cardiac high energy phosphate metabolism may lead to contractile dysfunction in heart failure. As the incidence of heart failure is increased in obesity, we have determined whether cardiac energy metabolism is abnormal in healthy, obese subjects. Methods and Results: Cardiac phosphocreatine (PCr) to ATP ratios and function were measured using magnetic resonance spectroscopy and imaging, respectively, in 20 asymptomatic obese adults and 19 age- and sex-matched controls. Fasting plasma leptin, glucose, insulin, C-reactive protein, lipid and free fatty acid (FFA) concentrations were also measured. With a mean body mass index (BMI) of 31 kg/m2, the obese subjects had 16% lower cardiac PCr/ATP ratios and 54% higher fasting plasma FFA concentrations than the control subjects, who had a mean BMI of 24 kg/m2. Multivariate stepwise linear regression analysis demonstrated that plasma FFA concentrations (β −0.5, P = 0.001) and BMI (β −0.3, P = 0.03) were significant independent predictors of the cardiac PCr/ATP ratio (model adjusted R2 = 0.46). The peak filling rate, a measure of diastolic dysfunction, correlated with the cardiac PCr/ATP ratio (r = 0.42, P = 0.013). Conclusions: Uncomplicated obesity is associated with decreased cardiac PCr/ATP ratios, diastolic dysfunction and increased plasma FFA concentrations, raising the possibility that abnormal cardiac high energy phosphate metabolism may contribute to the increased incidence of heart failure in obesity.
Abstract 580: Skeletal Myoblasts and Bone Marrow-Derived Cells Enhance the Contractile Function of Isolated Failing Cardiomyocytes in Co-culture
Authors: Joon Lee, Mark A Stagg, Gopal K Soppa, Urszula Siedlecka, Magdi H Yacoub, Cesare M Terracciano
Journal: Circulation (2006)

Cell transplantation has been shown to enhance ventricular function in heart failure. However, the low numbers of surviving transplanted cells can not explain the functional myocardial improvement directly, and the cellular mechanisms responsible remain unknown. We hypothesized that transplanted cells influence the native myocardium by paracrine mechanisms, and investigated the in vitro effects of bone marrow mononuclear cells or skeletal myoblasts on neighboring cardiomyocytes isolated from a rat model of heart failure. Myocardial infarction was induced in adult female Sprague-Dawley rats by left coronary artery ligation. Left ventricular ejection fraction after 3 weeks was 35.5 ± 2.0%. Isolated left ventricular myocytes were cultured (density 5.2 cells/mm 2 ) on their own (Control) or with either bone marrow mononuclear cells (BM, density 52 cells/mm 2 ) or skeletal myoblasts (SK, density 5.2 cells/mm 2 ). After 48 hours of culture with SK or BM cardiomyocyte relaxation speed was increased (time to 50% relaxation, in ms - Control 34 ± 6 [ 28 ]; BM 18 ± 3 [ 16 ] p &lt; 0.05 vs Control; SK 13 ± 2 [ 20 ] p &lt; 0.05 vs Control). The decay time course of the Ca 2+ transient, assessed by indo-1 fluorescence, was also hastened by SK (time to 50% decay, in ms – HF 22 ± 2 [ 29 ]; BM 18 ± 2 [ 17 ] ns ; SK 13 ± 1 [ 17 ] p &lt; 0.05 vs Control). SK also increased the contraction amplitude compared to Control (sarcomere shortening, in μm - HF 0.046 ± 0.006 [ 28 ]; BM 0.055 ± 0.01 [ 16 ] ns ; SK 0.091 ± 0.014 [ 20 ] p &lt; 0.05 vs Control). We conclude that bone marrow mononuclear cells and skeletal myoblasts enhance cardiomyocyte function in co-culture, demonstrating that paracrine mechanisms are involved. This may account for the functional improvement seen after cell transplantation.
Abstract 4951: A Genetic Model of Vascular Inflammation: Switchable Expression of Hypoxia Inducible Factor1 Alpha (HIF1a) Produces Multistage Targetable Endothelial Activation
Authors: Jeffrey M Arbeit, Andrea C Santeford, Sunday S Oladipupo, Megan M Kaneda, Gregory M Lanza, Samuel A Wickline
Journal: Circulation (2009)

Angiogenesis is a linchpin of survival and tissue restoration following ischemia, but also a prerequisite for atherosclerosis. Angiogenesis is induced by a complex interplay of tissue hypoxia, acidosis, and inflammation; conditions coordinated by a myriad of molecular regulators. We have created a switchable transgenic model of microvascular network elaboration allowing day-to-day kinetic analysis. Doxycycline induction of a Tet-regulated constitutively active hypoxia-inducible factor-1a mutant transgene, HIF-1a ^Pro402/564A/Asn803A was targeted to the skin (TetOn-HIF-1a mice). These mice first demonstrate microvascular dilatation on Dox d1, a burst of endothelial proliferation on d3, followed by an exponential decline by d14 –28. Plasma levels of the bone marrow mobilization factors VEGF, PlGF, and SDF1 spike on d3, while tissue levels of these recruitment and retention factors peak at d14. HIF-1 conditioned stroma and activated endothelium recruit large numbers of bone marrow-derived cells of multiple monocytic lineages. There is a striking, day/stage specific decoration of TetOn-HIF-1a microvessels by targeted nanoparticles. AlphaVbeta3 integrin-targeted nanoparticle binding is evident on d3, but absent by d14. VCAM-1-targeted nanoparticles display similar kinetics peaking on d3 (see Figure ); falling to background levels by d14. Thus, a monogenetic perturbation of a master regulatory transcription factor recapitulates the complex multitissue compartmental contributions to ischemic angiogenesis, providing a platform for functional investigation of the biology and therapeutic efficacy of inflammation with vascular-targeted nanoparticles. Figure 1. Decoration of the d3 TetOn-HIF- 1a microvasculature by Alexa Fluor 594 loaded, VCAM targeted, PFOB nanoparticles.
In Vivo Kinetics of Embryonic Stem Cell Viability Following Transplantation Into the Injured Murine Myocardium
Authors: Jaehoon Chung
Journal: Circulation (2009)

Abstract #250 Jaehoon Chung, Kehkooi Kee, Joelle K Barral, Rajesh Dash, Irving Weissman, Thomas Quertermous, Robert C Robbins, Dwight G Nishimura, Renee A Reijo-Pera, Phillip C Yang, Stanford University, Stanford, CA Jaehoon Chung, 2009 Finalist and Presenting Author
Abstract 588: Attenuation of Flow- and Nitrate-mediated Vasodilation in End-stage Renal Disease by Inflammation, Hyperphosphatemia and Hyperparathyroidism: Correction with Fall in C-reactive Protein by Nocturnal Hemodialysis
Authors: Christopher Chan, Paula Harvey, Andreas Pierratos, John S Floras
Journal: Circulation (2006)

Background: Endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIV) are impaired in end-stage renal disease (ESRD), yet improve soon after conversion from conventional (CHD) to nocturnal hemodialysis (NHD). Methods and Results: To test the hypotheses that suppression of inflammation and correction of hyperphosphatemia contribute to such improvement, dialysis dose, blood pressure (BP), brachial artery EDV and EIV, plasma C reactive protein (CRP), phosphate (Pi) and parathyroid hormone (PTH) were determined before, 1 and 2 months after conversion to NHD (n=23; mean age: 43±2 years [mean±SEM]). NHD increased dialysis dose, EDV and EIV (all p&lt;0.05) and lowered simultaneously measured BP, Pi and PTH (all p&lt;0.05) and CRP (from 14.8±3.9 to 6.63±2.1 mg/L after 2 months, p&lt;0.01). Overall, there was a significant inverse relationship between EDV and log 10 CRP (r=−0.35, p=0.008). Pre-specified dichotomization by CHD Pi identified higher BP with Pi &lt;1.8mM (n=10): (147±10/87±7 vs. 131±4/75±2 mmHg, p&lt;0.01), yet after 1 month both groups were normotensive. In those with Pi &lt;1.8mM, 1 month of NHD lowered CRP and increased EDV from −2.4±2.4 to 7.5±1.8% (p&lt;0.05). In contrast, in the high Pi group, NHD lowered Pi (p&lt;0.05) but had no significant effect on CRP, PTH or EDV (−0.8±1.1 vs. −0.6±1.6 %) but after 2 months, Pi and PTH fell and EDV and EIV improved. Conclusions: Correction of uremia and hypertension alone does not improve endothelial and smooth muscle brachial artery dilation in ESRD; contributions of systemic inflammation, altered Pi balance and hyperparathyroidism to impaired EDV and EIV must also be addressed. We provide the first demonstration that NHD reduces CRP.
Abstract 5043: Telmisartan Enhances Mitochondrial Biogenesis and Protects From Endothelial Cell Damage Through Peroxisome Proliferator-Activated Receptor- <i>γ</i> Independent Pathways
Authors: Toshimitsu Nozaki, Seigo Sugiyama, Koichi Sugamura, Hisao Ogawa
Journal: Circulation (2009)

Background Mitochondrial dysfunction in endothelial cells (EC) might be involved in atherogenesis. Telmisartan (TELMI), which has peroxisome proliferator-activated receptor (PPAR)- γ activating properties, has been shown to reduce cardiovascular events in high risk patients. We investigated whether TELMI could modulate mitochondrial function in human coronary artery endothelial cells (HCAEC). Methods and Results Pretreatment of HCAEC with 10 μ M TELMI preserved the mitochondrial function from H 2 O 2 exposure (1.0mM, 60min) evaluated by mitochondrial nicotinamide adenine dinucleotide (NADH) levels (NADH: 1.3±0.2 fold greater than vehicle, n=6, p&lt;0.01), and also reduced apoptotic annexin V positive EC induced by H 2 O 2 (100 μ M, 30min) (% apoptosis EC: vehicle 38.3±3.1%, TELMI 26.0±2.3, n=6, p&lt;0.01). TELMI increased EC mitochondrial number as assessed by fluorescence intensity of MitoTracker Green (vehicle 17.5±0.7, TELMI 21.3±2.1, n=6, p&lt;0.01) and enhanced EC mitochondrial function as assessed by colorimetric NADH assay, in a time and concentration dependent manner (0–48 hours, 0.1–10 μ M, up to 1.9±0.1 fold, n=7, p&lt;0.01), but other sartans did not have the similar effects. In senescent HCAEC at the 16 th passage, TELMI inhibited the appearance of giant EC (vehicle 44.3±5.2/field; TELMI 0.8±1.0, n=6, p&lt;0.01). TELMI treatment significantly enhanced EC tube formation (tube length: 4.1±0.4 fold greater than vehicle, n=5, p&lt;0.01), and we observed significant increases in mRNA expression levels of eNOS, VEGFA, mitochondrial transcription factor A, and Sirt1 in HCAEC after 48 hours TELMI treatment (1.3±0.2, 2.0±0.5, 1.2±0.04, 1.3±0.2 fold, respectively, all p&lt;0.05). To determine the possible involvement of PPAR γ pathway, we knocked down PPAR γ with siRNA and inhibited PPAR γ -mediated signaling by selective PPAR γ blockers; GW9662 and T0070907. These two strategies did not affect the increased mitochondrial NADH levels induced by TELMI. Consistently, GW1929, a selective PPAR γ agonist, did not alter mitochondrial function in HCAEC. Conclusion TELMI upregulates mitochondrial function in human EC through PPAR γ independent signaling mechanisms. TELMI could exhibit anti-atherogenic effects through improving mitochondrial dysfunction in EC.
Abstract 4880: Novel Role of P90RSK-mediated Sentrin/Sumo-specific Proteases 2 (SENP2) Phosphorylation on Disturbed Flow and H2O2-induced Apoptosis in Endothelial Cells
Authors: Kyungsun Heo, Nhat Tu Le, Hakjoo Lee, Chang-Hoon Woo, Patrizia Nigro, Eugene Chang, Carolyn McClain, Keigi Fujiwara, Juni-ichi Abe
Journal: Circulation (2009)

The atheroprotective roles of steady laminar flow (s-flow) and its inhibition against pro-inflammatory responses and endothelial cells (EC) apoptosis has been extensively studied. Emerging evidence suggested that disturbed flow (d-flow) and reactive oxygen species (ROS) are critical factors to induce EC dysfunction, which includes changes in vasoregulation, inflammatory activation, and altered barrier function with EC apoptosis. However, it remains unclear how d-flow induces EC dysfunction. We performed a survey of which kinases can be activated by d-flow, but not s-flow. We found that two kinases, p90RSK and PKC ζ , were particularly activated under d-flow, but not s-flow in EC. D-flow and H2O2 (50 μ M) significantly increased apoptosis in EC (5.79±0.5 fold compared with control; p&lt;0.01). Interestingly, we found that H2O2 increased nuclear export of p53 and p53-Bcl2 binding. The contribution of p53-SUMOylation on p53 nuclear export has been reported, and cytosolic p53-Bcl2 binding inhibits Bcl2 anti-apoptotic effect and induces apoptosis. Overexpression of p90RSK increased p53-SUMOylation, and adenovirus containing dominant negative form of p90RSK (Ad-DN-p90RSK) transduction significantly inhibited H2O2-mediated p53-SUMOylation, p53 nuclear export, p53-Bcl2 binding, and apoptosis, suggesting the critical role of p90RSK in p53-SUMOylation and subsequent apoptosis. Since four isoforms of p90RSK have similar function in EC, we used DN-p90RSK instead of siRNA which may downregulated all the isoforms. In addition, we determined SENP2 as a novel target of p90RSK based on the following results; depletion of SENP2 increased p53-SUMOylation and apoptosis in EC, overexpression of p90RSK significantly decreased SENP2 de-sumoylation activity, H2O2-mediated SENP2 nuclear export was significantly inhibited by Ad-DN-p90RSK transduction, and in vitro kinase assay showed that SENP2 was a good substrate of p90RSK. Finally, en face confocal microscopy analysis using apoE−/− mice also revealed the activation of p90RSK and the up-regulation of p53 expression at d-flow, but not at s-flow area, supporting the patho-physiological consequence of p90RSK-SENP2 and subsequent apoptosis on d-flow-mediated acceleration of atherosclerosis.
Abstract 4935: <i>Ex vivo</i> Acidic Preconditioning Modulates Bone Marrow-derived ckit <sup>+</sup> Cell Function <i>in vitro</i> and Enhances Their Therapeutic Potential in a Mouse Model of Hindlimb Ischemia
Authors: Chiara Cencioni, Roberta Melchionna, Stefania Straino, Marta Romani, Claudia Cappuzzello, Valentina Annese, Angela Santoni, Monica Napolitano, Maurizio C Capogrossi
Journal: Circulation (2009)

Background and Objective . Bone marrow-derived cell transplantation may provide a novel strategy for the treatment of cardiac and limb ischemia. However, in some cases cells appear to have lost their therapeutic potential and there is an interest in identifying interventions that are clinically applicable and may enhance cells’ ability to repair damaged tissues. The objective of the present work was to examine whether ex vivo acidic preconditioning (AP) may modulate bone marrow-derived ckit + cell functions in vitro and their regenerative properties in a mouse model of hindlimb ischemia. Methods and results. ckit + cells were obtained from 4-week old mice; AP was achieved by exposing cells to hypercarbic acidosis (buffer pH 7.0) for 24 hours and subsequently returning them to pH 7.4. Control ckit + cells (C) were always kept at pH 7.4. AP enhanced CXCR4 mRNA levels (2.5-fold vs C; n=6; p&lt;0.05). In agreement with this result AP increased SDF-1-driven chemotaxis (2-fold vs C; n=6; p&lt;0.02) and transendothelial migration (10-fold vs C; n=5; p&lt;0.05) as well as SDF-1-driven differentiation toward the endothelial lineage as indicated by DiI-Ac-LDL uptake (2.2-fold vs C; n=10; p&lt;0.005), vWF positivity (2.2-fold vs C; n=4; p&lt;0.005) and KDR positivity (3-fold vs C; n=4; p&lt;0.005). The effect of AP on ckit + cell therapeutic potential was examined in a mouse model of hindlimb ischemia. Either AP or C cells (5 × 10 5 ) were injected into the adductor muscle at the time of femoral artery dissection. AP cells accelerated blood flow recovery vs C cells as determined by laser doppler perfusion imaging at different time points throughout the 14-day time course following acute ischemia (n=8; p&lt;0.01 vs C). Further, 14 days after surgery, AP cells increased capillary (1.3-fold vs C; n=6; p&lt;0.01) and arteriole number (4.6-fold vs C; n=6; p&lt;0.01) as well as the number of regenerating muscle fibers measured 7 days after surgery (4.4-fold vs C; n=6; p&lt;0.05). Conclusions. ckit + cells exposed to AP exhibit enhanced CXCR4 expression and SDF-1-directed cell responses in vitro and regenerative properties in a mouse model of hindlimb ischemia. Thus, AP may represent a simple, unexpensive and clinically applicable strategy to improve the therapeutic efficacy of bone marrow-derived cell transplantation.
Resveratrol Improves Myocardial Perfusion in a Swine Model of Hypercholesterolemia and Chronic Myocardial Ischemia
Authors: Michael P. Robich
Journal: Circulation (2009)

Abstract #4220 Michael P. Robich, Beth Israel Deaconess Med Ctr, Boston, MA; Frank W. Sellke, Alpert Medical Sch of Brown Univ, Providence, RI Michael P. Robich, 2009 Finalist and Presenting Author
Abstract 5064: Endothelial-Specific Deletion of Cx40 Promotes Atherosclerosis by Increasing CD73-Dependent Leukocyte Adhesion
Authors: Christos E Chadjichristos, Ludwig Scheckenbach, Maya Z Richani Sarieddine, Isabelle Roth, Marc Bacchetta, Cor de Wit, Toon A van Veen, Marc Chanson, Brenda R Kwak
Journal: Circulation (2009)

Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. Here, we sought to determine whether Cx40 contributes to the development of the disease. Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Tie2CRE+ Cx40fl/fl ApoE−/− mice; EC-Cx40del mice). EC-Cx40del mice were indeed not hypertensive. The progression of atherosclerosis was increased in EC-Cx40del mice after 10 weeks high-cholesterol diet; lipid deposition in the thoracic-abdominal aortas was 21.4±3.5% (N=10, p&lt;0.01) in EC-Cx40del mice as compared to 12.6±1.3% for Tie2CRE+ Cx40wt/wt ApoE−/− and 7.1±1.3% for Tie2CRE- Cx40fl/fl ApoE−/− controls. Moreover, spontaneous lesions were observed in the aortic sinuses of young EC-Cx40del mice without diet. These lesions showed monocyte infiltration into the intima, increased expression of VCAM-1 and decreased expression of the ecto-enzyme CD73 in the endothelium. The pro-inflammatory phenotype of EC-Cx40del mice was confirmed in another model of induced leukocyte recruitment from the lung microcirculation. The number of leukocytes that migrated to the alveolar space in response to intratracheal instillation of LPS was markedly enhanced (p&lt;0.001) in EC-Cx40del mice compared to controls, both 3 and 6 hours after the treatment. Endothelial CD73 is known to induce anti-adhesion signaling via the production of adenosine. We found that reducing Cx40 expression in vitro with siRNA or anti-sense decreased CD73 expression and activity, and increased leukocyte adhesion to mouse endothelial cells (p&lt;0.01). These effects were reversed by an adenosine receptor agonist. A control siRNA or Cx40 sense had no effect on leukocyte adhesion. We suggest that Cx40-mediated gap junctional communication contributes to a quiescent non-activated endothelium by propagating adenosine-evoked anti-inflammatory signals between endothelial cells. Alteration in this mechanism by targeting Cx40 promotes leukocyte adhesion to the endothelium, thus accelerating atherosclerosis.
Abstract 587: Impaired Renal Function is not only related to Decreased Cardiac Output but also to Increased Venous Pressure in Patients with Cardiac Dysfunction
Authors: Kevin Damman, Tom D Smilde, Adriaan A Voors, Wim van der Bij, Gerjan Navis, Dirk J van Veldhuisen, Hans L Hillege
Journal: Circulation (2006)

Introduction: Glomerular filtration rate (GFR) is an important prognostic variable in chronic heart failure (CHF). CHF is associated with increased venous congestion and decreased cardiac output. The latter results in decreased renal blood flow (RBF). While the relationship between RBF and GFR is well established, little is known about the relationship between venous congestion and GFR. Hypothesis: We assessed the hypothesis that venous congestion plays a significant contributing role in determining renal function in patients with cardiac dysfunction. Methods: We studied 51 patients (30% male, mean age 40 ± 11 years), with cardiac dysfunction due to pulmonary hypertension. Right heart catheterisation was done to investigate right atrial pressure (RAP), mean pulmonary artery pressure, pulmonary vascular resistance (PVR) and cardiac index. GFR and RBF were measured by iothalamate and hippuran clearances, respectively. Results. Mean age was 40 ± 11 years and 69% of patients was female. Mean GFR was 73 ± 19 ml/min/1.73m 2 with a mean cardiac index of 2.1 ± 0.7 l/min/m 2 . In univariate analysis, RBF, RAP, cardiac index and PVR were related to GFR. In multivariate analysis, RBF ( r = 0.664, p &lt; 0.001) and RAP (r = − 0.367, p &lt; 0.020) were independently associated with GFR, accounting for 61% of the variability in GFR. Especially in patients with lower values of RBF, increased RAP was an important determinant of GFR (Figure ). Conclusion. RBF remains the most important factor associated with GFR in patients with cardiac dysfunction. However, especially in patients with low RBF, venous congestion indicated by an increased RAP plays a significant role in predicting GFR.
Abstract 574: Protein-Protein Interactions between Components of the Cardiac Ryanodine Receptor Complex and their Impairment by Genetic Defects Linked to Sudden Cardiac Death
Authors: Dmitry Terentyev, Srikanth Vedamoorthyrao, Radmila Terentyeva, Simon C Williams, Sandor Gyorke
Journal: Circulation (2006)

Intracellular Ca release in cardiac muscle is mediated by a mutimolecular complex composed among other proteins of the ryanodine receptor (RyR) channel, the integral proteins triadin (TRD) and junctin and the Ca binding proteins calsequestrin (CASQ2), which is also known to form polymers required for high capacity-intrastore Ca binding. Mutations of these proteins result in disregulated myocyte SR Ca release, cardiac arrhythmia and sudden death. We used fluorescence resonance energy transfer (FRET) and fusion constructs utilizing the cyan and yellow fluorescent proteins (CFP and YFP, respectively) as donor-acceptor pairs to investigate interactions between TRD and CASQ2 and between CASQ2 monomers in a heterologous expression system (3T3 cells). All fusion constructs were localized to the stores of the endoplasmic reticulum. When coexpressed, CFP-TRD and YFP-CASQ2 exhibited FRET the efficiency of which depended on the Ca loading state of the intracellular Ca stores. FRET efficiency was high when the stores were depleted and low when stores were Ca loaded, thus revealing a negative dependency of TRD-CASQ2 interaction on [Ca]. Cotransfection of CFP-CASQ2 and YFP-CASQ2 resulted in FRET with an efficiency that increased at high Ca store loads and decreased at low store loads, consistent with positive dependence of CASQ2-mulimerization. Expression of two different CASQ2 mutants (R33Q and G112+5X) linked to sudden cardiac death specifically affected the ability of CASQ2 either to interact with TRD or to polymerize. These results indicate that functionally- relevant interactions exists between components of the multimolecular RyR Ca release channel complex. These interactions could provide a molecular basis for the dynamic control of SR Ca release by intra-store Ca and for defective SR Ca release caused by mutations of CASQ2 to cause CPVT.