tbuckley/cabot-search huggingface dataset:
Abstract 590: Abrogation of Nuclear Factor-Kappa B Activation in the Heart Alleviates Post-Infarction LV Remodeling
Authors: Tariq Hamid, Xilin Xiang, James P Marshall, Ernest Cardwell, Guangwu Wang, Buddhadeb Dawn, Sumanth D Prabhu
Journal: Circulation (2006)

The failing heart is characterized by chronic activation of nuclear factor (NF)-κB, a central transcriptional mediator of inflammatory and stress responses. As NF-κB can signal to either survival or apoptotic pathways, however, whether such activation confers cardioprotective or detrimental effects is unknown. We tested the hypothesis that sustained activation of NF-κB exacerbates LV remodeling in heart failure (HF). We examined LV remodeling following permanent coronary ligation (or sham-operation) in adult male transgenic (TG) mice with NF-κB abrogation in the heart via the cardiac-specific overexpression of a phosphorylation-resistant IκBα (n=16), or in non-transgenic (NTG) littermates (n=16). Baseline echocardiography showed no inherent cardiac phenotype in the TG mice. Compared to NTG sham, 4 weeks after surgery, NTG HF hearts showed: increased (p &lt; 0.01) LV size (EDV 94 ± 35 vs. 35 ± 5 μL) and systolic dysfunction (LVEF 50 ± 9 vs. 75 ± 7 %) by echocardiography; hypertrophy (LV/tibia length [TL] 5.3 ± 0.7 vs. 3.7 ± 0.3, p &lt; 0.001; ~2-fold greater atrial natriuretic factor [ANF] mRNA, p &lt; 0.05); significantly (p &lt; 0.05) increased (~2-fold) NF-κB DNA binding activity and mRNA levels of the NF-κB-responsive cytokines tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6; and increased apoptotic rates by TUNEL staining (1.1 ± 0.5 vs. 0.03 ± 0.03%, p &lt; 0.05). In contrast, compared to NTG HF, TG HF hearts had markedly reduced (p &lt; 0.01) NF-κB DNA activation, and significantly less (p &lt; 0.05) LV dilatation (LVEDV 52 ± 20 μL) and systolic dysfunction (LVEF 61 ± 8 %), but a similar degree of hypertrophy as assessed by LV/TL and ANF expression. Moreover, as compared to TG sham, TG HF hearts exhibited no TNF, IL-1β, or IL-6 upregulation. Importantly, as compared to TG sham, TG HF showed only a mild increase in apoptotic rate (0.4 ± 0.3 %) that was not statistically significant (p = 0.45), suggesting that differences in the rate of cell loss between NTG and TG HF may account for comparable degrees of chamber hypertrophy despite differences in LV dilatation. Conclusion: Persistent NF-κB activation imparts detrimental effects in post-infarction HF and worsens LV remodeling, related, at least in part, to augmentation of inflammatory cytokine expression and apoptosis.
Abstract 5105: Increased Glucose Uptake in Visceral versus Subcutaneous Adipose Tissue Revealed by PET Imaging
Authors: Thomas Christen, Viviane Rocha, Yuri Sheikine, Allison Goldfine, Marcelo Di Carli, Peter Libby
Journal: Circulation (2009)

Background : The amount of visceral and subcutaneous adipose tissue (VAT and SAT, respectively) differentially predicts cardiovascular risk. Beyond volumetric measurement, glucose uptake in adipose tissue might yield additional information for risk stratification. This study explored differences in glucose utilization between VAT and SAT and potential mechanisms for this finding. Methods and Results : Retrospective analysis of whole body FDG-PET scans from 59 patients showed that VAT exhibited higher FDG uptake than SAT (Figure A , p&lt;0.0001) independent of age, gender, body mass index, co-morbidities, or medications. To investigate the mechanisms underlying this observation, we then studied glucose uptake in stromal vascular cells (SVCs), a fraction of the adipose tissue which is rich in inflammatory cells. SVCs from VAT of diet-induced obese C57BL/6 mice exhibited higher glucose uptake than those from SAT (Figure B , n=6, p=0.01). Evaluation of the expression of various genes involved in cellular glucose metabolism such as glucose transporters (GLUT 1, 3 and 4) and hexokinases (HK-1 and 2) showed increased expression of HK-1 in VAT-compared to SAT-derived SVCs (Figure C , n=10, p=0.005). This finding illustrates one mechanism that may explain the above results. Conclusions: This study showed non-invasively with FDG PET imaging that VAT has increased glucose uptake compared to SAT in human subjects, and showed experimentally that inflammatory cells may contribute to this difference. These findings add to our understanding of the nexus between adiposity, inflammation, and cardiovascular risk.
Abstract 5432: Inhibition of Hif Prolyl 4-hydroxylases Protect Against Reoxygenation Injury in Endothelial Cells
Authors: Tatyana Dimitrova, Frauke V Haertel, Aslam Muhammad, Anna Reis, Hans M Piper, Thomas Noll
Journal: Circulation (2009)

Background: Hypoxia inducible factor-1 (Hif-1 α ) modulates expression of genes essential for cell survival under hypoxia. The oxygen-sensing enzyme prolyl 4-hydroxylase2 (PHD2) targets Hif-1 α for destruction under normoxia. Hypoxia/Reoxygenation is associated with p53 activation, a master regulator of apoptosis in many type of cells. We hypothesized that preservation of Hif-1 α beyond the period of hypoxia protects endothelial cells from reperfusion injury. To analyze the protective effect of Hif-1 α , human umbilical veins endothelial cells were exposed to 1 h of hypoxia (Po2&lt;5mmHg) followed by 24 hrs of reoxygenation (Reox.; Po2=140mmHg). Exposure to hypoxia causes a increase in Hif-1 α , p53, and Mdm2 (E3 ubiqitin ligase) by 3.1±0.2, 2±0.3, and 1.9±0.2-fold compared to control, respectively. During Reox. Hif-1 α and Mdm2 declined towards basal level, while p53 remained unaltered. Under the same conditions endothelial apoptosis was increased to 47±3% (annexin V staining). Silencing of PHD2, (53% reduction of PHD2 content) lead to an increase of the Hif-1 α content during hypoxia and maintained it at that level during Reox. Hif-1 α stabilization was accompany by an increase in the Mdm2 content and phosphorylation, whereas expression of p53 was reduced. PHD2 silencing reduced apoptosis to half. Additon of DMOG (1mM dimethyloxalylglycine), a PHD inhibitor, at the onset of Reox had the same effect. Reduction of p53 content was restored when the proteosome inhibitor MG-132 was added. Interaction of Mdm2 and P53 (co-immunoprecipitation) was increased compare to Reox. Downregulation of Hif-1 α by siRNA (64% reduction of Hif-1 α content) increased apoptosis to 66±5% and abrogate Mdm2-p53 complex formation. Downregulation of Mdm2 by siRNA (38% reduction of content) had no effect on Hif-1 α but increased p53 level. Conclusions: siRNA downregulation as well as pharmacological inhibition of PDH2, manoeuvre which inhibit Hif-1 α degradation and maintained it at that level during Reox. protect against reperfusion injury. This effect of Hif-1 α involves stimulation of Mdm2 induced degradation of the proapoptotic p53.
Abstract 5267: The Annexin A5 Homodimer Diannexin Protects Against Ischemia Reperfusion Injury Through Phosphatidylserine Binding
Authors: Kimberley E Wever, Karina Claassen, Cathelijne Frielink, Otto Boerman, Gert-Jan Scheffer, Anthony Allison, Frank Wagener, Rosalinde Masereeuw, Gerard A Rongen
Journal: Circulation (2009)

Renal ischemia/reperfusion injury (IRI) frequently complicates cardiac and aortic surgery and has prognostic significance. The translocation of phosphatidylserines (PS) to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed PS by the annexin A5 homodimer Diannexin protects against renal IRI. Mice (n =8 – 10) underwent 20 min bilateral clamping of the renal pedicle, followed by 3 or 8 days of reperfusion. Either 200 ug/kg Diannexin or vehicle was injected i.v. 20 min prior to ischemia. Renal injury peaked on day 3 post-op. When compared to vehicle, Diannexin treatment reduced the IRI-induced glucosuria, prevented the increase in urine flow, reduced the proximal tubule damage and reduced the expression and/or transcription of the renal injury markers Neutrophil Gelatinase Associated Lipocalin (NGAL) and Kidney Injury Molecule-1 (KIM-1; see table ). Reduced KIM-1 expression persisted on day 8 after Diannexin treatment [0.23±0.02 vs. 0.36±0.06; p&lt;0.05]. To confirm PS as the target for Diannexin, mice (n=2– 6) underwent unilateral IRI of the hind limb. Upon reperfusion, 4.5 ug Tc-99m-Diannexin was injected i.v. . Diannexin targeted specifically to the ischemic limb when compared to the control limb [4.0±0.60 vs. 0.2±0.02 %ID/g; p&lt;0.001]. Targeting could be reduced by a preceding injection of 500 ug unlabeled annexin A5 [1.5±0.3 vs. 0.7±0.2 %ID/g], suggesting that Diannexin targets to ischemic tissues via PS binding. This study indicates the importance of PS exposition in IRI. We conclude that Diannexin protects against renal IRI by binding to PS, making it a promising tool to prevent IRI in a clinical setting. Table: effects of Diannexin on functional, histological and injury marker parameters after renal IRI
Abstract 5222: Genetic Deficiency of Arginase II Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice
Authors: Young Jun Oh, Jae Hyung Kim, Sungwoo Ryoo, Gautam Sikka, Daniel Berkowitz
Journal: Circulation (2009)

Introduction: Arginase II is known to be one of the key mediator in vascular pathophysiology of cholesterol-medicated endothelial dysfunction by reciprocal regulation of NOS and NO production through substrate competition. We aimed to investigate whether the transgenic Arginase II inhibition could reduce the endothelial dysfunction and atherosclerosis in apolipoprotein E-knockout (ApoE-KO) mice. Methods and Results: ApoE-KO mice were bred on an arginase II KO (ArgII-KO) background. Mice that were homozygous deleted at both alleles were used in the study. Male 8 – 12 wk old Arg-KO mice, ApoE-KO mice, Arg/ApoE-KO (Dbl-KO) mice fed high cholesterol diet for 16 weeks, and age-matched wild type (WT) mice fed normal diet were enrolled. Arginase activity was significantly higher in the aorta of ApoE-KO mice than compared to WT mice (1612.2±445.9 pmol Urea/mg protein/min vs. 836.3±12.2 pmol Urea/mg protein/min, n=5, p &lt; 0.01), but not detected in Arg-KO and Dbl-KO mice. We measured NO an ROS in vascular strips pinned down endothelial side up using the fluorescent probes DAF-FM diacetate and DHE. Dbl-KO mice showed significantly higher NO production (0.0737±0.0056 intensity/sec vs. 0.0256±0.0029 intensity/sec, n=6, p &lt; 0.05) and lower ROS production than ApoE-KO mice (0.0676±0.0065 intensity/sec vs. 0.1147±0.01619 intensity/sec, n=6, p &lt; 0.05). We tested endothelial dependent vasorelaxation in aortic rings in organ chambers. The vasorelaxation response to acetylcholine (Ach) in Dbl-KO mice was greater than in ApoE-KO mice (log EC 50 , −5.68 vs. −5.13, p &lt;0.05), although it was less than in Arg-KO and WT mice. N G -nitro-L-arginine methyl ester (L-NAME) incubation didn’t only impair Ach response, but also abolished the inter-group difference. The aortic atheromatous plaque burden as measured by Sudan IV staining was significantly reduced in Dbl-KO group compared to ApoE-KO group (38.4±3.8% vs. 52.0±2.8%, n=6, p &lt;0.01), No significant plaque was detectable in Arg-KO and WT mice. Conclusion: The genetic inhibition of Arginase II enhanced NO production, reduced ROS produnction restored endothelial function and lowered atheromatous plaque burden. Therefore, Arginase II represents a crtical novel target for atherosclerosis therapy.
Abstract 5124: Renal Function and Cardiac Structure and Function in Hypertensives With Established Diastolic Dysfunction in the VALIDD and EXCEED Trials
Authors: Amil M Shah, Hajime Uno, Amira H Hassanein, Anil Verma, Akshay S Desai, Ricardo A Rocha, Robert Hilkert, Joseph Izzo, Suzanne Oparil, Bertram Pitt, James D Thomas, Michael R Zile, Gerard P Aurigemma, Scott D Solomon
Journal: Circulation (2009)

Background : Impaired in renal function is associated with increased risk of cardiac events. The relationship between mild impairments in renal function and degree of diastolic dysfunction (DD) has not been well established. Methods : Estimated glomerular filtration rate (eGFR), urine albumin-to-creatine ratio (ACR) and echocardiographic measures were assessed in 597 subjects with stage 1 or 2 hypertension, no heart failure, and DD by reduced mitral annular early relaxation velocity (E′) enrolled in the VALIDD (n=381) and EXCEED (n=216) trials. Both trials tested different BP reduction strategies for improvement in DD. Results : eGFR was ≤60 ml/min/1.73m 2 in 80 subjects (13%), 61–75 in 130 (22%), and &gt;75 in 387 (65%). Decreasing eGFR was significantly associated with lower E′ (p=0.0033), higher E/E′ (p=0.0252), higher LA volume index (p=0.0117), smaller LV volume (p&lt;0.0001), and higher NT-proBNP (p=0.0042). ACR was undetectable in 149 subjects (27%), 1– 4 in 130 (24%), 5–9 in 93 (17%), 10 –30 in 104 (19%), and &gt;30 in 75 (14%). Increasing ACR was associated with lower E′, higher LV mass, increased LV wall thickness, and higher NT-proBNP even after adjustment for age, gender, race, and differences in 7 baseline characteristics (p&lt;0.014 for all associations). In combined analysis, both eGFR (p=0.0166) and ACR (p=0.0019) were independent predictors of baseline E′, without evidence of significant interaction. Conclusions : Among hypertensive subjects with DD, mild impairments of eGFR and elevated levels of albuminuria are associated with greater degrees of DD. Both eGFR and albuminuria are additive and independently associated with worse DD.
Abstract 4842: Is Altered Collagen Turnover Related to the Development of Stiff Arteries and Hearts in Chronic Kidney Disease?
Authors: Nicola C Edwards, Helen Kirkwood, Robert Cramb, Richard P Steeds, Charles J Ferro, John N Townend
Journal: Circulation (2009)

Introduction Cardiovascular mortality is increased in chronic kidney disease (CKD) in a graded inverse relationship with glomerular filtration rate (GFR). We and others have demonstrated increased arterial stiffness which also has a graded relationship with GFR and is of prognostic significance. Experimental studies have shown increased collagen associated proteins in the intimal and medial arterial layers which appear to precede vascular calcification in CKD. We hypothesised that active, collagen dependent, fibrotic processes might increase arterial stiffness and compromise ventricular relaxation thereby contributing to the high levels of cardiovascular disease. Methods We studied 117 patients with early stage CKD (mean eGFR 51 ml/min/1.73m 2, range 30 – 89), controlled hypertension (&lt;130/85mmHg) no history of cardiovascular disease or diabetes. Arterial stiffness was assessed using pulse wave velocity (PWV) by applanation tonometry and aortic distensibility in the ascending aorta by CMR (1.5T). Early myocardial relaxation velocities (Em) and E/Em ratio (marker of LVEDP) were measured by echocardiography. Serological collagen turnover markers; amino-terminal propeptide of procollagen type III (PNIIIP a measure of collagen synthesis) and C-terminal telopeptide of type I collagen (CTx a measure of collagen degradation), were measured by radioimmunoassay and ECLIA immunoassay. Results PNIIIP was inversely correlated with eGFR ( r = 0.52 p&lt;0.01), aortic distensibilty ( r = 0.23 p&lt;0.05) and Em ( r = 0.24 p&lt;0.05) and positively correlated with PWV ( r = 0.23 p&lt;0.05), and E/Em ( r = 0.2 p&lt;0.05). CTx was inversely correlated with eGFR ( r = 0.31 p&lt;0.01) but was not correlated with markers of arterial or ventricular stiffness Conclusion Collagen synthesis, arterial and ventricular stiffness are all increased with deteriorating renal function even from the earliest stages of CKD. This suggests that collagen metabolism plays an important role in the development of arterial and myocardial stiffness in CKD. Collagen turnover is a possible new therapeutic target in the prevention of cardiovascular disease in CKD.
Abstract 5123: Assessment of Myocardial Microvascular Abnormalities in Chronic Kidney Disease
Authors: Michael A Kuliszewski, Dmitriy Rudenko, Kim A Connelly, Darren Yuen, Judy Trogadis, Richard E Gilbert, Howard Leong-Poi
Journal: Circulation (2009)

Recent data has shown that chronic kidney disease (CKD) has been linked to the development of cardiovascular disease and been associated with an adverse prognosis. It has been hypothesized that effects on the coronary microcirculation play a critical role in the exacerbation of disease. Thus, we assessed the myocardial microvasculature in CKD, using fluorescent microangiography (FMA) and myocardial contrast echocardiography (MCE). Methods: 8 week old male Fischer 344 rats underwent subtotal nephrectomy (n=10) (SNX), or sham surgery (n=10). Systolic blood pressure (SBP), proteinuria, left ventricular (LV) ejection fraction (EF), end-diastolic pressure volume relationship (EDPVR) and Tau were assessed at baseline and 8 weeks following surgery. MCE was performed to assess regional myocardial perfusion, and rats were subjected to FMA (10% solution of 0.02 μ m fluorescent microspheres). Thick (200 μ m) sections of fixed tissue can then be visualized under confocal microscopy. Stacks of images are collected and 3D reconstruction and visualization carried out in order to quantify the density, size and shape of blood vessels. An automated tracing algorithm was used to create a solid 3D model. Results : SNX animals showed increased in SBP and urinary protein confirming CKD. LVEF was preserved (68±16 versus 53±14 % in controls), while diastolic function was impaired in both the energy-dependent early (Tau) (16.7±3.1 versus 11.0±1.2 msec; p&lt;0.05) and late passive EDPVR, a measure of LV compliance (0.052±0.026 versus 0.018±0.009 mmHg/ul in controls; p&lt;0.01). FMA analysis illustrated a reduction in average vessel diameter (3.84±0.08 versus 4.68±0.16 μ M in controls; p &lt; 0.05), and a reduction in vascular density (2.81E-03±1.72E-04 versus 3.63E-03±1.56E-04 μ M in controls; p &lt; 0.01). MCE-derived endocardial-epicardial blood flow ratio was reduced in CKD as compared to sham controls (0.67±0.14 versus 1.12±0.35 in controls; p&lt;0.05). Conclusion: Myocardial microvascular loss occurs in CKD, and is associated with a reduction in endocardial blood flow and impaired diastolic function, with preserved LV systolic function.
Abstract 577: S100A1 Decreases Calcium Spark Frequency and Alters their Spatial Characteristics in Ventricular Cardiomyocytes
Authors: Mirko Völkers, Christopher M Loughrey, Nial MacQuaide, Brent de George, Walter J Koch, Godfrey L Smith, Patrick Most
Journal: Circulation (2006)

Background: S100A1, a Ca 2+ -sensor protein of the EF-hand type, exerts positive inotropic effects in the heart via enhanced cardiac ryanodine receptor (RyR2) activity. Although we have shown that S100A1 enhances excitation-contraction coupling gain in cardiomyocytes, the effect of S100A1 on diastolic RyR2 activity and SR Ca 2+ -leak has not been investigated yet. Methods and Results : Confocal imaging and coimmunoprecipitation studies show that S100A1 protein (0.1μM) interacts with the RyR2 in resting permeabilized cardiomyocytes at free Ca 2+ -levels comparable to diastolic Ca 2+ -concentrations (~150nM). Preincubation with the S100A1 C-terminus (S100A1-ct, aa 75–94, 10μM) inhibited both S100A1 protein colocalization and coimmunoprecipitation with the RyR2. Alterations of RyR2 function due to S100A1 binding was assessed via analysis of Ca 2+ -spark characteristics. Ca 2+ -spark frequency, amplitude and duration were all significantly reduced upon perfusion with 0.1μM S100A1 protein (n=350 sparks, n=12 myocytes) by 38%, 14% and 18%, respectively, compared to control (n=336 sparks, n=10 myocytes, p&lt;0.05). Most likely, these effects were conveyed through the S100A1 C-terminus (S100A1-ct; amino acids 75–94) as the corresponding S100A1-ct peptide (0.1μM, n=374 sparks, n=12 myocytes) that inhibited S100A1 protein binding to the RyR2 similarly attenuated frequency, amplitude and duration of Ca 2+ -sparks by 52%, 8% and 26%, respectively, compared to control (n=368 sparks, n=10 myocytes, p&lt;0.05). Accordingly, S100A1 (n=15) significantly increased sarcoplasmic reticulum Ca 2+ -content (+15%, p&lt;0.05) but did not alter the stoichiometry of other accessory RyR2 modulators such as sorcin or FKBP12.6 as assessed by Western blotting. Conclusion: Hence, we propose S100A1 as a novel inhibitory modulator of RyR2 function at diastolic Ca 2+ -concentrations in cardiomyocytes that might contribute to prevention of diastolic SR calcium leak through inhibition of RyR2 activity at rest but enhances the calcium-activated state of the channel in systole.
Abstract 568: Formation of Cardiac Fibers in Matrigel Matrix
Authors: Karina Bakunts, Zaruhi Karabekian, Narine Sarvazyan
Journal: Circulation (2006)

INTRODUCTION. BD Matrigel Matrix is a basement membrane preparation extracted from the Engelbreth-Holm-Swarm mouse sarcoma, a tumor rich in extracellular matrix proteins. At room temperature, the matrigel polymerizes to produce a biologically active matrix material resembling the mammalian cellular basement membrane. Matrigel is widely used for cellular attachment, cell invasion assays and as a component of cell differentiation media. Here we report a new means for its use. METHODS. Matrigel is employed to create in vitro cardiac fibers from rat neonatal cardiomyocytes. A semi-solid “pillow” from concentrated matrigel is overlaid with a cardiomyocyte suspension in a diluted matrigel solution. Myocytes submerged in the top matrigel layer form multicellular structures of different sizes. The underling semi-solid matrigel creates an elastic environment which serves as a mechanical load against which myocytes contract. RESULTS. This new technique creates a net of actively contracting multicellular fibers which can be maintained in vitro for up to six weeks. Presented data illustrate the appearance and development of these fibers. Dependence of the fiber size on myocyte amount and matrigel concentration is also described. CONCLUSIONS. This new semi-3D model of cardiac muscle offers the ease of both structural and functional monitoring since fiber thickness of 50 –300 micron makes these structures suitable for live confocal microscopy (calcium and potentiometric indicators) and gives easy assess to the epitopes for immunostaining purposes.