tbuckley/cabot-search huggingface dataset:
Abstract 5080: Role of Mineralocorticoid Receptor/Rho/Rho-kinase Pathway in Obesity-Related Renal Injury
Authors: Hirobumi Tokuyama, Shu Wakino, Satoru Tatematsu, Kyoko Yoshioka, Kazuhiro Hasegawa, Yoshikazu Hara, Hitoshi Minakuchi, Keiko Sueyasu, Koichiro Homma, Naoki Washida, Koichi Hayashi, Hiroshi Itoh
Journal: Circulation (2009)

Both aldosterone and Rho-kinase are demonstrated independently to play an important role in renal injury and impaired insulin signalling. We therefore examined whether aldosterone/Rho/Rho-kinase pathway contributed to obesity-associated nephropathy. C57BL/6J mice were fed a high fat (HFD) or low fat diet (LFD) and mice on HFD were treated with a mineralocorticoid receptor (MR) antagonist, eplerenone. The mice on HFD developed obesity, and hyperglycemia compared with those on LFD, but manifested similar levels of systolic blood pressure. In HFD-fed mice, glomerular hypercellularity and increased mesangial matrix were noted (66.7±3.0 vs. 32.3±2.5 nuclei/gcs, p&lt;0.01), which paralleled the increase in albuminuria (HFD, 0.13±0.04mg/gCr, P&lt;0.01 vs LFD, 0.02±0.01mg/gCr). The treatment with eplerenone alleviated the histological changes and albuminuria (0.04±0.01mg/gCr, P&lt;0.01 vs HFD) without alterations in systemic blood pressure. Adipose tissue weight and adipocyte size of HFD-fed mice were increased, which were ameliorated by eplerenone. Furthermore, enhanced Rho-kinase activity was noted in kidneys (2.0-fold, p&lt;0.05) and adipose tissues (1.8-fold, p&lt;0.05) from HFD-fed mice, as well as increased expressions of MCP-1, TNF- α and PDGF-B. All of these changes were attenuated by eplerenone. In HFD-fed mice, MR protein levels in the nuclear fraction were increased in kidneys (2.3-fold, p&lt;0.05) and adipose tissues (2.0-fold, p&lt;0.05) without elevation in serum aldosterone levels (LFD, 278±14mg/dl, HFD, 297±12mg/dl), and Sgk1, an effector of aldosterone, was upregulated (kidneys; 5.5-fold, p&lt;0.01, adipose tissues; 2.2-fold, p&lt;0.01). Finally, in mesangial cells, stimulation with aldosterone increased Rho-kinase activity, and pre-incubation with eplerenone prevented the aldosterone-induced activation of Rho-kinase. In conclusion, excess fat intake causes obesity and renal injury in C57BL/6J mice, and these changes are mediated by enhanced MR/Rho/Rho-kinase pathway and subsequent inflammatory process. Furthermore, both MR activation and the subsequent Rho-kinase stimulation are likely to participate in the development of obesity-associated nephropathy without elevation in serum aldosterone levels.
Abstract 193: Role of Sarcoplasmic Reticulum Calcium Cycling in Arrhythmias in a 2-D Experimental Model of Calcium Overload
Authors: Marvin G Chang, Connie Y Chang, Linmiao Xu, Rajesh B Sekar, Josh Cysyk, Eduardo Marbán, Leslie Tung, M. Roselle Abraham
Journal: Circulation (2006)

Ca 2+ overload and/or altered sarcoplasmic reticulum (SR) Ca cycling has been argued to underlie ventricular tachyarrhythmias seen in patients with mutations of RyR2 and calsequestrin2 as well as heart failure. Aim : We investigated the role of SR Ca cycling on triggered activity and spiral wave dynamics in a 2-D model of Ca overload. Methods: We studied control neonatal rat ventricular myocytes (NRVM-only) monolayers and co-cultures of skeletal myoblasts and NRVMs. Initially, Ca overload was induced by superfusion with BAYK8644 (BayK, 2.5μM) and Isoproterenol (ISO, 1μM) for 5 mins. Subsequently, SR Ca cycling was modulated by 10mM caffeine for 5 min followed by Caffeine + 1μM thapsigargin (CAF/THAP) for 5 mins. Triggered activity and reentry were induced by rapid pacing. Optical mapping (voltage or Ca imaging) was performed. Degree of meandering was assessed using mutual information analysis of tip trajectories. Results : Ca imaging during 2Hz pacing revealed that caffeine produced a sharp rise in Ca transients followed by a return to steady state pre-caffeine levels; addition of CAF/THAPS produced a sharp and permanent decrease in Ca transients. Triggered activity (DADs) was observed in co-cultures (n=10) and controls (n=10) with 3–5 Hz pacing in the presence of BAYK/ISO. In co-cultures, DADs occurred from 2 or more sites and tended to drift; pseudo EKGs resembled polymorphic VT, while in controls it was stationary and pseudo EKGs resembled monomorphic VT. Surprisingly, DADs continued to occur even after abolition of SR Ca cycling by CAF/THAPS. Caffeine (n=4) significantly increased reentry pathlength (PL) by 59% but did not significantly change reentry cycle length (CL), conduction velocity (CV), wavelength (WL), or wavefront curvature. Addition of CAF/THAP (n=3) increased reentry WL by 17%, PL by 73%; decreased reentry CV by 28% and increased tip meandering without affecting reentry CL. Additional rotors and wavebreaks were observed during perfusion of BayK/ISO as well as after addition of CAF/THAP; power spectrum showed a single dominant frequency. Conclusion : DADs can occur from cytoplasmic Ca overload even in the absence of SR Ca cycling. Abolition of SR Calcium cycling in the presence of BayK/ISO produced wavebreak but did not induce spiral wave breakup.
Abstract 566: Altered Expression of Connexin43 Contributes to the Arrhythmogenic Substrate in Early Stage Heart Failure of Cardiomyopathic Hamster
Authors: Takashi Sato, Tomoko Ohkusa, Haruo Honjo, Shinsuke Suzuki, Yuko S Ishiguro, Harumichi Nakagawa, Masatoshi Yamazaki, Masafumi Yano, Itsuo Kodama, Masunori Matsuzaki
Journal: Circulation (2006)

Background: Heart failure is known to predispose life-threatening ventricular tachyarrhythmias even before compromising the systemic circulation, but the underlying mechanism is not well understood. Methods and Results : We investigated stage-dependent changes in connexin43 (Cx43) expression and consequent electrophysiological properties in UM-X7.1 cardiomyopathic hamster hearts. UM-X7.1 hamsters develop left ventricular (LV) hypertrophy by age 6~10w, and show more pronounced LV hypertrophy and a moderate reduction in LV contractility at age 20w. Appreciable interstitial fibrosis is recognized at these stages. LV mRNA and protein levels of Cx43 in UM-X7.1 were unaffected at 10w, but significantly reduced at 20w (by 33% and 55%, respectively from controls). The relative expression level of serin255-phosphorylated Cx43 was markedly increased in UM-X7.1 at age 20w (by 175%). Electrophysiological properties were examined by optical mapping. In UM-X7.1 at 10w, almost normal LV conduction was preserved, whereas the dispersion of action potential duration (APD) was significantly increased. UM-X7.1 at 20w showed significant reduction of conduction velocity (by 35~40%), significant prolongation of APD (by 68%), marked distortion of activation fronts and a pronounced increase in APD dispersion. Programmed stimulation resulted in no arrhythmias in controls, but sustained ventricular tachycardia or fibrillation (VT/VF &gt;5s) in UM-X7.1 (1/11 at 10w and 5/6 at 20w). LV activation during polymorphic VT was characterized by multiple phase singularities or wavebreaks. Conclusions : In the early stage heart failure of cardiomyopathy, down-regulation and serine255-phosphorylation of Cx43 in addition to the interstitial fibrosis may contribute to the arrhythmogenic substrate through the inhibition of cell-to-cell communication.
Abstract 4200: Does Homocysteine Lowering Impact Cardiovascular Outcomes? A Bayesian Meta-Analysis of NORVIT and HOPE-2 Trials
Authors: Sanjay Kaul, Andrew A Zadeh, George A Diamond, Prediman K Shah
Journal: Circulation (2006)

Background: In HOPE-2 trial, homocysteine lowering with B vitamins failed to reduce clinical outcomes compared to placebo except for a significant reduction in stroke (P=0.03). The stroke benefit was thought to “represent either an overestimate of the real effect or a spurious result due to play of chance, and that a meta-analysis should be able to clarify the issue”. Objective: To perform a Bayesian meta-analysis by integrating prior information from the NORVIT trial with the empirical evidence from HOPE-2 (the only 2 large completed placebo-controlled trials of homocysteine lowering). Methods: Posterior probabilities that the benefit (P b ) or harm (P h ) exceeds a specified difference (δ&lt;0%, 10%) were estimated via the Bayes’ theorem: posterior α evidence x prior. Only data from comparison of combination vitamin therapy group vs placebo was utilized from NORVIT to match the HOPE-2 treatment groups for primary composite endpoint of cardiovascular death, myocardial infarction (MI) or stroke and the individual endpoints. Superiority or inferiority was inferred at a posterior probability of benefit or harm &gt;0.950. Results: The P h exceeded P b for the primary composite endpoint and each of the individual components except for stroke where the probability of any benefit (δ&gt;0%) was 0.992 and the probability of &gt;10% risk reduction (δ&gt;10%) was 0.930. Conclusions: Thus, a Bayesian meta-analysis helps clarify the issue, and suggests a low likelihood of coronary benefit and a high likelihood of stroke benefit with homocysteine-lowering therapy compared to placebo. These data are consistent with the epidemiologic observations of a stronger association of elevated homocysteine with stroke compared to CAD (adjusted odds ratio of 1.32 (1.18–1.49) vs 1.19 (1.12–1.25) for +5μmol/L increase in homocysteine level observed in prospective studies). Ongoing trials should further clarify the impact of homocysteine lowering.
Abstract 4186: The Association of Central Obesity With Sex Hormones Differs Between Men and Women in the MultiEthnic Study of Atherosclerosis (MESA)
Authors: Dhananjay Vaidya, Pamela Ouyang, Adrian S Dobs, Sherita H Golden, Moyses Szklo, Kiang Liu, Susan M Gapstur
Journal: Circulation (2006)

Sex hormones affect adipose tissue metabolism and adipose tissue also metabolizes sex hormones for local effects. Central obesity is associated with a pro-atherogenic metabolic state. We analyzed cross sectional associations of endogenous sex hormones (SH: bioavailable Testosterone, BioT; estradiol, E2; dehydroepiandrostenedione, DHEA; SH binding globulin, SHBG) with waist circumference (WC) or waist to hip ratio (WHR) in men and women. Methods: Analysis included 3163 men and 2051 postmenopausal women who were not on hormone therapy, (45– 84 years, 36% white, 13% Chinese, 28% African-American, 23% Hispanic) at MESA baseline examination. Analyses of interaction by sex were performed on the whole as well as race-stratified dataset. Estimations of association measures were done on sex-stratified race-pooled models. Unadjusted associations were assessed by Spearman rank correlations. WC (or WHR) was regressed on log-transformed SH adjusted for age, race, systolic BP, smoking and fasting glucose. Results: The WC was 99.2±12.2cm in men and 98.6±15.6cm in women (p= 0.100). WHR was higher in men (96±7%) than women (92±8%, p&lt;0.001). We found an unadjusted negative association of WC with BioT in men, but in women the association was positive (Table , Spearman rho). DHEA was negatively associated with WC in men. In both men and women, E2 was positively associated and SHBG was negatively associated with WC. In adjusted models (Table , coefficients), the findings for BioT, E2 and SHBG remained, while DHEA was associated with lower WC in both men and women. Sex differences were similar in race-stratified models. The interactions by sex were qualitatively similar for WHR in pooled and race stratified models. Conclusions: In men and women, E2 is associated with greater central obesity, while DHEA and SHBG are associated with lower central obesity. This suggests that the hypoandrogenic state may be metabolically favorable in women, but unfavorable in men. Waist Circumference and Sex Hormones in MESA
Abstract 4908: Athero-protective Effects of Immunization With apoB-100 Related Peptide Vaccine in apoE−/− Mice is Associated With Enhanced CD8 Regulatory T Cell Response
Authors: Xiaoning Zhao, Kuang-Yuh Chyu, Paul C Dimayuga, Juliana Yano, Xiaojun Li, Portia Trinidad, Jianchang Zhou, Wai Man Lio, Jonathan Kirzner, Lai F Chan, Bojan Cercek, Prediman K Shah
Journal: Circulation (2009)

Background: We previously reported that immunization of apoE−/− mice with human apoB-100 related peptide P210 (KTTKQ SFDLS VKAQY KKNKH) resulted in a 60% reduction in atherosclerosis by a regulatory T-cell (Treg) response elicited by the vaccine. In this study, we investigated the mechanisms involved in this regulatory response. Methods and Results: Male apoE−/− mice were immunized at 6, 9 and 11 weeks of age with P210 conjugated to cBSA, and alum as adjuvant, at a dose of 0.1 mg/mouse and euthanized at 13 weeks of age, or fed atherogenic diet until euthanasia at 25 weeks of age. At 13 weeks, FACS analysis of regional LN showed significantly reduced CD11c + CD86 + dendritic cells (DC) in the p210 group (Table ), suggesting an immune-regulatory response. Treg profiling showed significantly increased CD8 + CD25 + Treg in the peripheral blood (PBMC) of P210 group (Table ) without changes in the CD4+CD25+ and CD8+CD28- Treg. CD11c+ DCs in atherosclerotic lesions at 25 weeks were reduced in P210 (2.9± 1.7%, n = 12; p&lt;0.05) compared with cBSA or PBS group (3.9± 1.6%, n = 7 and 4.5± 1.2%, n = 18; respectively) with concomitant reduction of macrophages in P210 group compared with cBSA and PBS (12.4± 2.5% vs. 15.4± 3.1% and 16.1± 2.9%, respectively; p&lt;0.05). Conclusion: Our results indicate that P210 vaccination resulted in a CD8+CD25+ Treg response mediated by decreased DC co-stimulatory signaling, leading to a reduction of plaque DC and macrophage content, and attenuated plaque growth, suggesting a novel role of CD8+ Treg in reducing atherosclerosis.
Abstract 4914: Extracellular SOD-derived H <sub>2</sub> O <sub>2</sub> Promotes VEGF Signaling via Oxidative Inactivation of Protein Tyrosine Phosphatases Localized in Caveolae/Lipid Rafts
Authors: Jin Oshikawa, Nihal Kaplan, Masooma Razvi, Norifumi Urao, Ronald McKinney, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation (2009)

Reactive oxygen species (ROS), in particular, H 2 O 2 , is essential for full activation of VEGF receptor2 (VEGER2) signaling involved in endothelial cell (EC) proliferation and migration. Extracellular superoxide dismutase (ecSOD) is a major extracellular antioxidant enzyme in the vasculature that converts superoxide to H 2 O 2 . It is secreted and anchored to the endothelial surface through binding to the heparan sulfate proteoglycan (HSPG), which binds to VEGFR2 to facilitate its signaling. Mice lacking ecSOD show impaired postnatal angiogenesis. However, underling mechanism remains unknown. Here we show that adenovirus-mediated ecSOD overexpression in cultured medium in ECs enhances VEGF-induced tyrosine phosphorylation of VEGFR2 (VEGFR2-pY) (2.9-fold). This ecSOD-induced effect is prevented by short-term pretreatment with catalase which scavenges extracellular H 2 O 2 . Of note, either exogenous H 2 O 2 or mutant ecSOD lacking heparin binding domain (ecSOD-deltaHBD) has no effect on VEGF-induced VEGFR2-pY, suggesting that H 2 O 2 needs to be produced close to VEGFR2 for its activation. Mechanistically, VEGFR2 as well as protein tyrosine phosphatases (PTPs) PTP1B and DEP1, which negatively regulate VEGFR2, but can be inactivated by ROS, are colocalized in caveolae/lipid rafts. VEGF-induced VEGFR2-pY in these microdomains is enhanced by ecSOD (2.3-fold), which is associated with oxidation of PTP1B and DEP1, and decrease in PTPs activity (48.9%) in caveolae/lipid rafts. PTPs inhibitor orthovanadate; or siRNAs for PTP1B and DEP1; or disruption of caveolae/lipid rafts by methyl-b-cyclodextrin enhances VEGF-induced VEGFR2-pY, which prevents ecSOD-induced effect. Functionally, ecSOD significantly promotes VEGF-stimulated EC migration (1.7-fold) and proliferation (1.4-fold). In vivo, adenovirus ecSOD injection into adductor muscle improves blood flow recovery and increases capillary formation after hindlimb ischemia, while mutant ecSOD-deltaHBD has no effects. In summary, H 2 O 2 produced proximity to VEGFR2 by ecSOD inactivates PTPs in caveolae/lipid rafts via oxidation, thereby promoting VEGF-induced VEGFR2-pY and angiogenesis. Thus, ecSOD is important therapeutic target for angiogenesis-dependent cardiovascular diseases. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota &amp; Wisconsin).
Abstract 4194: Low-Dose Aspirin Reduces Cardiovascular Events and All-Cause Mortality Among Patients with Stable Cardiovascular Disease: A Meta-Analysis
Authors: Jeffrey S Berger, David L Brown, Richard C Becker
Journal: Circulation (2006)

Background: The Antithrombotic Trialists’ Collaboration meta-analysis demonstrated that anti-platelet therapy reduced cardiovascular events in patients with prior cardiovascular disease. However, in that analysis, stable and unstable patients were grouped together, all anti-platelet agents were combined and most of the aspirin studies used a dose higher than currently recommended (&gt;325mg/day). The effect of low-dose aspirin (50–325mg/day) in patients with stable cardiovascular disease has not been reported. Methods: Secondary prevention trials of low-dose aspirin in patients with stable cardiovascular disease were identified by searches of the MEDLINE database from 1966 to 2006. Six randomized trials were identified that enrolled patients with a history of myocardial infarction (n=1), stable angina (n=1) and a stroke or transient ischemic attack (n=4). A random effects model was used to combine results from individual trials. Results: The 6 studies randomized a total of 9,853 patients. Aspirin therapy was associated with a significant 21% reduction in the risk of cardiovascular events (non-fatal MI, non-fatal stroke and cardiovascular death) (Odds Ratio (OR) 0.79, 95% Confidence Interval (CI) 0.72– 0.88, P&lt;0.01), 26% reduction in the risk of non-fatal MI (OR, 0.74, 95% CI, 0.60– 0.91, P&lt;0.01), 25% reduction in the risk of stroke (OR, 0.75, 95% CI, 0.65– 0.87, P&lt;0.01) and a 13% reduction in the risk of all-cause mortality (OR, 0.87, 95% CI, 0.76– 0.98, P=0.03).Based on these data, treatment of 30 patients with low-dose aspirin is required to prevent 1 cardiovascular event, 83 patients to prevent 1 non-fatal MI, 40 patients to prevent 1 stroke and 71 patients to prevent 1 death. Patients treated with aspirin were significantly more likely to experience severe bleeding (OR, 2.2, 95% CI, 1.4–3.4, P&lt;0.01). The number needed to harm from severe bleeding is 111 patients. Conclusion: Among patients with stable cardiovascular disease, low-dose aspirin therapy reduces the incidence of adverse cardiovascular events and all-cause mortality, while increasing the risk of severe bleeding. The protective effect of aspirin supports current recommendations that all patients with stable cardiovascular disease be placed on low-dose aspirin.
Abstract 582: Cardiac Fibroblast Bridges Conduct Electrical Signals between Myocyte Islands.
Authors: Ponthetta Mitchell, Thomas K Borg, Robert G Gourdie, Bruce Z Gao
Journal: Circulation (2006)

In this study, the electrophysiological properties of fibroblasts cocultured with cardiomyocytes were characterized using a novel cell micropatterning system. In the infarct area of a heart, the cardiac fibroblasts are known to increase collagen deposition leading to fibrosis. The fibrous tissue acts as an insulator in the damaged area and thus modulates local electrical signal conduction. This is fibroblast’s “passive role” in myocardium signal conduction. However, studies have shown that when placed in physical contact with viable myocytes, fibroblasts can form functional gap junctions and conduct electrical signal. This coupling phenomenon has been suggested as playing a role in re-entrant arrhythmias that occur in the infarct to healthy tissue border zone but there is still little known about the actual involvement fibroblasts have in the heart’s electrical communication. Our interest is in designing an in vitro model using cell micropatterning to study and characterize the electrophysiological properties of fibroblasts cocultured with myocytes. In this study we evaluate the hypothesis that fibroblast will conduct electrical signal between myocytes but this conduction will be restricted by the number of fibroblast involved. A combination of photolithography and laser micropatterning is used to achieve cell micropatterning. Polydimethyl siloxane (PDMS) stencils, created by photolithography, are used to form the myocyte islands and laser micropatterning is used to form the fibroblast cell bridge connecting the myocyte islands. Various PDMS stencils which varied the distance between the myocyte islands were made enabling us to form fibroblast bridges of various lengths (50 um to 500 um). Dual patch clamp experiments were performed to evaluate action potential propagations along the fibroblast bridge and characterize its electrical capabilities. With our laser micropatterning we were able to form fibroblast conducting bridges up to 390 um. In conclusion, fibroblast bridges can conduct electrical signals over short distances however with the increase of the fibroblast bridge length, signal propagation delay also increased. This conduction delay phenomenon observed in vitro could explain the cause of reentrant arrhythmias in vivo.
Abstract 4953: Del-1, a New Beta2-integrin Ligand, Which Inhibits Mobilization, Adhesion and Homing of Progensitor Cells
Authors: Emmanouil Chavakis, Andreas Hain, Alessia Orlandi, Guillaume Carmona, Thomas Quertermous, Triantafyllos Chavakis, Stefanie Dimmeler
Journal: Circulation (2009)

Progenitor cells (PC) are recruited to ischemic tissues and improve neovascularization. Beta2-integrins are essential for adhesion and homing of PC to ischemic tissues. Developmental Endothelial Locus-1 (Del-1) is an extracellular matrix protein that binds alphaVbeta3-and beta2-integrins and is up-regulated during ischemia. Therefore, we investigated the role of Del-1 for angiogenesis and homing functions of PC. Del-1-deficient mice (Del-1−/−) displayed a significantly increased angiogenic response in ischemic muscles in comparison to the wild type (WT) mice in the model of hind limb ischemia. However, when we assessed the role of Del-1 in HUVEC in vitro, silencing of Del-1 by siRNA did not affect angiogenic sprouting. Moreover, the ischemic muscles of Del-1−/− mice displayed a higher infiltration with CD45+ cells than WT mice, suggesting that Del-1-deficiency may induce activation of homing of PC and inflammatory cells to ischemic tissues. Interestingly, in adhesion assays human endothelial progenitor cells (EPC) and murine Lin- PC bound to Del-1 via beta2-integrins, but not via the alphaVbeta3-integrins. Furthermore, soluble Del-1 significantly inhibited the adhesion of EPC to HUVEC monolayers and to the major beta2-integrin-ligand, ICAM-1. Moreover, WT murine bone marrow (BM) mononuclear cells displayed higher adhesion rates on Del-1-deficient murine lung endothelial cells (LEC) than on WT LEC. In order to investigate the role of Del-1 for in vivo homing of PC, we intravenously injected murine fluorescence-labeled WT Lin- BM PC in WT and Del-1−/− mice 2 days after the induction of hind limb ischemia. Interestingly, the homing of injected Lin- cells to ischemic muscles was significantly increased in Del-1−/− in comparison to WT mice (200±30 % increase). Moreover, Del-1−/− mice displayed a significantly increased GCSF-induced mobilization of Sca1+ cKit+ PC in the peripheral blood in comparison to WT mice. Taken together, Del-1 is a new beta2-integrin ligand, which blocks PC mobilization and beta2-integrin-dependent adhesion and homing of PC to ischemic tissues. It is conceivable, that endogenous Del-1 may reduce ischemia-induced neovascularization through an inhibitory effect on the beta2-integrins of PC and inflammatory cells.