tbuckley/cabot-search huggingface dataset:
Abstract 5774: Hypoxia Enhances Platelet-derived Growth Factor Signaling in the Pulmonary Vasculature by HIF-1 <i>α</i> -dependent Downregulation of Protein Tyrosine Phosphatases
Authors: Henrik Freyhaus, Maike Leuchs, Markus Dagnell, Marius Vantler, Evren Caglayan, Norbert Weissmann, Ralph T Schermuly, Bhola K Dahal, Arne Östman, Kappert Kai, Stephan Rosenkranz
Journal: Circulation (2009)

Background: Platelet-derived growth factor (PDGF) plays a critical role in the development of pulmonary hypertension (PH) as it promotes pulmonary vascular remodeling. PH is frequently associated with severe pulmonary hypoxia. Here we investigated whether hypoxia alters PDGF β receptor ( β PDGFR) signaling. Methods and Results: Chronic hypoxia enhanced PDGF-BB-dependent proliferation and chemotaxis of human pulmonary arterial smooth muscle cells (hPASMC). Pharmacological inhibition of PI3 kinase (PI3K) and PLC γ abrogated these events both under normoxia and hypoxia. While hypoxia did not affect β PDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at the binding sites for PI3K (Y751) and PLC γ (Y1021). The activated β PDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Strikingly, hypoxia decreased the expression of numerous PTPs (TC-PTP, DEP-1, PTP1B, SHP-2), resulting in reduced PTP activity. Putative hypoxia-inducible factor (HIF)-1 α binding sites were identified in the promoter regions of the downregulated PTPs, and hypoxia-induced β PDGFR hyperphosphorylation and PTP downregulation were abolished by HIF-1 α siRNA and by the HIF-1 α inhibitor 2-methoxyestradiol. Immunohistochemistry and quantitative RT-PCR demonstrated that β PDGFR hyperphosphorylation and PTP downregulation were also present in vivo in mice with chronic hypoxia-induced PH. Conclusions: Hypoxia reduces the expression and activity of β PDGFR-antagonizing PTPs in a HIF-1 α -dependent manner, thereby enhancing receptor activation and proliferation/chemotaxis of hPASMC. As hyperphosphorylation of the β PDGFR and downregulation of PTPs also occur in vivo, this mechanism likely has significant impact on the development and progression of PH and other proliferative diseases.
Abstract 5776: Deletion of the Systemic Gp130-dependent Acute Phase Response Inhibits Neointima Formation Following Carotid Artery Ligation
Authors: Karsten Grote, Harald Schuett, Gustavo Salguero, Ezequiel Tallone, Helmut Drexler, Bernhard Schieffer
Journal: Circulation (2009)

Background: Inflammation and vascular remodeling are hallmarks of atherosclerosis, hypertension and restenosis following angioplasty. Recently we demonstrated a crucial role of the hepatocyte gp130-dependent systemic acute phase response for atherogenesis (JEM 2007). Now we have elucidated the role of the hepatocyte gp130-dependent systemic acute phase response for vascular remodeling following experimental carotid artery ligation. Methods and Results: Mice with a hepatocyte-specific gp130-k.o. on an apoE −/− background (gp130 − ) were compared to control mice (gp130 flox ). Vascular remodeling was induced by permanent ligation of the left common carotid artery. This activated the systemic acute phase reaction in gp130 flox mice as measured by acute phase serum amyloid A (SAA1) plasma levels and vascular SAA1 content and was completely abrogated in gp130 − mice (ELISA, SAA1 immunostaining, P&lt;0.05, n=5). Morphometric analysis of the carotid artery revealed severe neointima formation and media thickening 28 days post ligation in gp130 flox mice which was inhibited in gp130 − mice (P&lt;0.01, n=6). Carotid segments from gp130 − showed less smooth muscle cells (SMCs), proliferation and monocyte recruitment ( α -SMC actin, Ki-67, MOMA-2 immunostaining, P&lt;0.01, n=6). To evaluate the impact of the gp130-dependent systemic acute phase response on SMCs, hepatocytes from gp130 flox and gp130 − mice were stimulated with the gp130-activating interleukin (IL)-6. IL-6-induced secretion of SAA1 was completely abolished in gp130 − hepatocytes (ELISA, P&lt;0.01, n=4). Moreover, when stimulated with supernatants from gp130 − hepatocytes, SMCs showed significantly less migration and proliferation compared to supernatants from gp130 flox hepatocytes (transwell, scratch assay, BrdU-incorporation, P&lt;0.01, n=4). Finally, recombinant SAA1 induced SMC migration and proliferation (transwell, scratch assay, BrdU-incorporation, P&lt;0.01, n=3– 4) and SAA1-injection following carotid artery ligation restored vascular remodeling in gp130 − mice (P&lt;0.01, n=3–5). Conclusion : These results imply a critical role of the gp130-dependent systemic acute phase response for vascular inflammation, SMC migration and proliferation and subsequently for vascular remodeling.
Abstract 5782: Increased Cardiomyocyte Elasticity in the Transverse Direction in Hypertrophied Rat Hearts Induced by Chronic <i>β</i> -adrenergic Stimulation
Authors: Kazufumi Nakamura, Daiji Miura, Wakako S Yoshikawa, Ken Hashimoto, Noriyuki Kataoka, Juichiro Shiizu, Nobuhiro Nishii, Satoshi Nagase, Hiroshi Morita, Yoshiki Hata, Kengo F Kusano, Hiroshi Ito
Journal: Circulation (2009)

Background: Cardiomyocyte stiffness in longitudinal direction is increased in patients with diastolic heart failure. However, stiffness in transverse direction has not been elucidated. We hypothesized that cardiomyocyte elasticity in transverse direction is also increased in hypertrophied hearts. We measured the elasticity of a single cardiomyocyte by use of an atomic force microscope (AFM) in isoproterenol (ISO)-induced hypertrophied rat hearts. Methods and Results: Male Wistar rats (9 weeks old) received a vehicle (control), ISO (2.4 mg · kg −1 · day −1 ) or ISO + β 1-blocker metoprolol (MET) (24 mg · kg −1 · day −1 ) subcutaneously (n=5 in each group). After 7 days, compared with those in control and ISO+MET groups, ISO administration had increased left ventricular (LV) wall thickness (P&lt;0.05), and decreased LV diastolic function as assessed by increased LV end-diastolic pressure (ISO: 15.3±2.0 vs control: 4.8±0.5 or ISO + MET: 6.6±0.8 mmHg, P &lt;0.05). Elasticity of 10 living cardiomyocytes from LV free wall was measured by parabolic force curves of cantilever deflection/indentation obtained by AFM (Fig A ). Elasticity of cardiomyocytes was significantly higher in ISO group than in control and ISO + MET groups (Fig B ). Next, we added butanedione monoxime (BDM) (20 mM), an inhibitor of actin-myosin interaction, and blebbistatin (10 μ M), a specific myosin II inhibitor, to culture medium. BDM and blebbistatin significantly reduced the elasticity of cardiomyocytes in ISO group (Fig B ). Conclusions : Cardiomyocyte elasticity in transverse direction was increased in hearts with ISO-induced hypertrophy along with diastolic dysfunction. This may be caused by incomplete relaxation.
Abstract 5756: The MicroRNA-17–92 Cluster Exhibits a Cell Intrinsic Anti-angiogenic Function in Endothelial Cells
Authors: Carmen Döbele, Angelika Bonauer, Ariane Fischer, Yvonne Reiss, Andreas M Zeiher, Stefanie Dimmeler
Journal: Circulation (2009)

MicroRNAs (miRs) are endogenously expressed small noncoding RNA molecules that are able to regulate gene expression on the posttranscriptional level by binding to the mRNAs of their target genes, thus inducing inhibition of translation or mRNA degradation. The miR-17–92 cluster (encoding miR-17, -18a, -19a, -20a, -19b and miR-92a) was shown to augment tumor angiogenesis if overexpressed in tumor cells. Whereas miR-92a was recently identified as negative regulator of vessel growth, the individual functions of the other members of the miR-17–92 cluster in endothelial cells is less clear and only a combination of miR-17, -18a and -20a was shown to partially rescue the defective angiogenesis under conditions of Dicer deficiency. To investigate the involvement of the individual members of the miR-17–92 cluster in angiogenesis, human umbilical vein endothelial cells (HUVECs) were transfected with precursor molecules for miR-17, -18a, -19a and -20a. Overexpression of the different members significantly inhibited 3D spheroid sprouting (Pre-17:10±3%,-18a: 28±5%,-19a: 45±4%,-20a: 33±8% of control) and impaired the assembly of capillary networks in vitro. Conversely, inhibition of miR-17 (142±15% of control), miR-18a (152±6% of control) and miR-20a (153±9% of control) augmented spheroid sprout formation. Next, we addressed the in vivo relevance by using antagomirs to block the individual miRs. Antagomir-17 (which also blocks miR-20a) significantly increased the number of lectin-positive vessels in matrigel plugs (190±26% of control), whereas antagomirs, which specifically affect miR-18a and miR-19a were less effective. Antagomir-17 additionally improved blood flow after hind limb ischemia (217±24% of control) and increased tumor growth (140±14% of control). To identify direct targets of miR-17, we combined microarray gene expression analysis with target prediction. Among others, Janus kinase 1 (Jak1) was significantly downregulated on mRNA (38±5% of control) and protein (41±14% of control) level by miR-17. In summary, we show that the individual members of the miR-17–92 clusters exhibit a cell intrinsic anti-angiogenic activity in endothelial cells. Inhibition of miR-17 efficiently increased neovascularization and tumor growth in vivo.
2009 Katharine A. Lembright Award and Lecture—The Evolving Picture of Women With CHD
Authors: Jean McSweeney
Journal: Circulation (2009)

Although coronary heart disease is the No. 1 killer of women, an evidence-based picture of prodromal and acute myocardial infarction symptoms in ethnically diverse women is underdeveloped. This contributes to disparate outcomes, especially in minority women. Lack of recognition of early presenting symptoms associated with coronary heart disease and acute myocardial infarction on the part of women and their healthcare providers contributes to these poor outcomes because delayed recognition of symptoms limits options for efficacious treatment. This presentation will focus on the development of the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey (MAPMISS) that has been used with more than 2800 racially diverse women. This instrument, based on qualitative findings, includes 33 symptoms of prodromal coronary heart disease and 37 symptoms of acute myocardial infarction and questions related to frequency and severity of the symptoms. Women’s symptom experiences and difficulty receiving a diagnosis of coronary heart disease will be discussed. Comparison of both prodromal and acute myocardial infarction symptoms in black, Hispanic, and white women will be presented. The presentation will conclude with a cluster analysis, based on prodromal and acute myocardial infarction symptom scores calculated from symptom reports from more than 1500 women, that examines the association between racially diverse women’s characteristics and symptom clusters. These data make a significant contribution to the evolving picture of women’s prodromal and acute myocardial infarction symptoms.
Abstract 5045: Muscle-Type Capillary Endothelial Cells Actively Transport Fatty Acids via Intracellular Fatty Acid Binding Protein-4 and -5
Authors: Tatsuya Iso, Kazuhisa Maeda, Hirofumi Hanaoka, Toshihiro Suga, Hiroki Matsui, Kosaku Goto, Masashi Arai, Keigo Endo, Gohkan S Hotamisligil, Masahiko Kurabayashi
Journal: Circulation (2009)

Endothelial cells (EC) of muscle-type continuous capillary act as functional interface between the blood plasma and the tissue fluid. They have been considered to perform transendothelial exchange for many substances to transport them into interstitial compartment. Fatty acids are major source of energy metabolism in various organs including heart, skeletal muscle and adipose tissue, but it is uncertain how they can reach interstitial space through endothelial layer of capillary. Fatty acid binding proteins (FABP) are cytosolic fatty acid chaperones whose biological role is not fully understood. FABP4, also known as aP2, is believed to be exclusively expressed in adipocytes and macrophages while FABP5, also called mal1, is detected more widely. Thus far, we have reported that disrupted function of FABP4 and FABP5 in mice (double KO mice) exhibited a striking phenotype with strong protection from diet-induced obesity, insulin resistance and type 2 diabetes. Here we report an unexpected function of the FABPs in capillary EC. We first re-examined tissue distribution of the FABPs by immunohistochemistry. We found that in addition to highly expressing organs already reported, both FABP4/5 were strongly expressed in capillary EC, but not in any arteries, in heart, skeletal muscle, and adipose tissue. In mice deficient for either FABP4 or FABP5, or both, their expression was absent in capillary EC of the organs. Of interest, FABP5 expression was markedly enhanced in capillary EC in mice lacking FABP4, suggesting compensatory induction of FABP5. The tissue distribution of FABPs, along with the phenotype of the double KO mice, raised an intriguing possibility that capillary EC actively transport fatty acids from capillary lumen to interstitial compartment via intracellular FABP4 and FABP5. Consistent with this hypothesis, fatty acid metabolism was markedly reduced while glucose consumption was reciprocally and dramatically elevated in the heart (16.9 folds) and the skeletal muscle (3.7 folds) in the double KO mice, as estimated in vivo by uptake of fatty acid analog, 125 I-BMIPP, and glucose analog, 18 F-FDG. Considering the highest impacts of the FABPs in preventing the metabolic syndrome, this novel pathway may lend a new approach to treat the type 2 diabetes.
Abstract 5816: The Human Apoa-1 Transgene Suppresses Myeloid Proliferation and Accelerated Atherosclerosis in Ldlr Deficient Mice Reconstituted With ABC Transporter Deficient Bone Marrow
Authors: Laurent Yvan-Charvet, Tamara Pagler, Emmanuel Gautier, Serine Avagyan, Read Siry, Hans Snoeck, Gwendalyn Randolph, Alan R Tall
Journal: Circulation (2009)

Overexpression or infusions of apoA-1 or HDL lead to reduced atherosclerosis. A major mechanism to explain this effect is thought to be cholesterol efflux from arterial wall macrophage foam cells via ABC transporters. In this study we have tested this hypothesis by transplanting bone marrow deficient in ABCA1 and ABCG1 into atherogenic diet-fed Ldlr deficient mice with or without expression of a human apoA-1 transgene. Unexpectedly, the apoA-1 transgene dramatically suppressed the accelerated atherosclerosis as well as leukocytosis, monocytosis and myeloid cell infiltration of organs in mice receiving double KO bone marrow. Double KO bone marrow showed a 5-fold expansion of hematopoietic stem cells, increased cycling of stem cells, increased myeloid progenitor cells and increased proliferation of bone marrow myeloid cells in response to growth factors. Double KO bone marrow myeloid cells showed increased association of ras with the plasma membrane possibly reflecting increased cholesterol content on the inner leaflet of the plasma membrane and increased ERK signaling in response to IL-3 or GM-CSF treatments. HDL promoted cholesterol efflux and decreased Ras membrane association and ERK signaling and inhibited proliferation of both WT and double KO bone marrow myeloid cells. The findings indicate a novel mechanism in which HDL may suppress atherosclerosis by decreasing myeloid cell proliferation and consequent monocytosis.
Leptin and Soluble Leptin Receptor Levels in Plasma and Risk of Type 2 Diabetes in US Women: A Prospective Study
Authors: Qi Sun
Journal: Circulation (2009)

Abstract #897 Qi Sun, Rob M. van Dam, Harvard Sch of Public Health, Boston, MA; James B. Meigs, Massachusetts General Hosp, Boston, MA; Oscar H. Franco, Univ of Warwick, Coventry, United Kingdom; Christos S. Mantzoros, Beth Israel Deaconess Medical Ctr, Harvard Medical Sch, Boston, MA; Frank B. Hu, Harvard Sch of Public Health, Boston, MA Qi Sun, 2009 Finalist and Presenting Author
2009 Dickinson W. Richards Memorial Lecture—Improving Survival From Out-of-Hospital Cardiac Arrest
Authors: Karl Kern
Journal: Circulation (2009)

A renewed understanding of resuscitation physiology has led to several bold new approaches to basic life support (BLS) and advanced cardiovascular life support (ACLS), as well as a recognition that aggressive postresuscitation care can have a major impact on long-term outcome. Concepts initially tested in basic and translational resuscitation research laboratories have within the past several years been piloted in a number of rural and urban communities. Several of these newer approaches to BLS, ACLS, and postresuscitation care have dramatically increased historical survival rates around the world. These include the following: Hands-only BLS CPR . The survival rate for witnessed ventricular fibrillation in Tokyo increased from 11% to 19% when lay bystander rescuers performed chest compression– only or “hands-only” BLS as compared with chest compressions and mouth-to-mouth breathing. The American Heart Association endorsed “hands-only” BLS for encouraging more bystander CPR in March 2008. New ACLS algorithm emphasizing uninterrupted chest compressions . The initial report of the use of this newly revised ACLS approach came from rural Wisconsin. The rate of 1-year survival from witnessed ventricular fibrillation cardiac arrest tripled, from 15% to 48%. A follow-up report 3 years later showed a persistent benefit, with a 3-year survival rate of 40%. In Phoenix, Arizona, introduction of this revised ALCS algorithm increased the rate of survival to hospital discharge with ventricular fibrillation cardiac arrest from 12% to 28%. Postresuscitation care . Postresucitation care is the next great opportunity to improve long-term outcome among victims of out-of-hospital cardiac arrest. In Norway, the rate of 1-year survival among those resuscitated from out-of-hospital cardiac arrest increased from 26% to 56% after formalization of the postresuscitation care, with emphasis on providing mild therapeutic hypothermia and early catheterization and percutaneous coronary intervention where indicated. Case series reported in the literature suggest this approach can produce long-term survival rates of 70% among those initially resuscitated, with 80% of such long-term survivors being neurologically intact. The near future holds more real promise for improving the outcome of those suffering cardiac arrest than ever before. Now is the time to move forward and provide improved care to all victims of sudden cardiac death.
Clinical Implications of JUPITER in a United States Population: Insights From the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Eric Y Yang
Journal: Circulation (2009)

Abstract #896 Eric Y Yang, Vijay Nambi, Baylor Coll of Med, Houston, TX; Zhengzheng Tang, Univ of North Carolina, Chapel Hill, NC; Salim S. Virani, Baylor Coll of Med, Houston, TX; Eric Boerwinkle, Univ of Texas-Houston Sch of Public Health, Houston, TX; Ron C Hoogeveen, Baylor Coll of Med, Houston, TX; Brad C Astor, John Hopkins Bloomberg Sch of Public Health, Baltimore, MD; Thomas H Mosley, Univ of Mississippi Medical Ctr, Jackson, MS; Josef Coresh, John Hopkins Bloomberg Sch of Public Health, Baltimore, MD; Lloyd Chambless, Univ of North Carolina, Chapel Hill, NC; Christie M Ballantyne, Baylor Coll of Med, Houston, TX Eric Y Yang, 2009 Finalist and Presenting Author
Abstract 5799: Overexpression of Integrin Beta5 Enhances the Paracrine Angiogenic Properties of Early Outgrowth Endothelial Progenitor Cells via Src Kinase-Mediated Activation of STAT3
Authors: Maren Leifheit, Gaby Conrad, Nana-Maria Heida, Marco Schroeter, Gerd Hasenfuss, Stavros Konstantinides, Katrin Schaefer
Journal: Circulation (2009)

Integrin alphavbeta5 is expressed on endothelial (progenitor) cells and has been implicated in angiogenesis. We have previously shown that stimulation of endothelial progenitor cells (EPC) with leptin upregulates alphavbeta5 integrin expression and enhances their angiogenic and reparative properties. The aim of the present study was to determine the intracellular mechanisms mediating the angiogenic effects of integrin alphavbeta5 in endothelial progenitor cells. For this purpose, EPC isolated from human venous blood and cultivated under endothelial conditions were transiently transfected with the full-length cDNA of human integrin beta 5 (EPC-ITGB5) or empty vector control (EPC-control), and analyzed 48 hours later (on day 7). Integrin beta5 overexpression was confirmed using flow cytometry (149±12%; P=0.0001 vs. EPC-control), Western blot (138±10%; P&lt;0.01) and PCR analysis (135±13%; P&lt;0.05). Moreover, it significantly enhanced the angiogenic capacities of EPC in vitro (spheroid and matrigel angiogenesis assay) and stimulated new vessel formation in vivo (chorioallantoic membrane assay and murine hindlimb ischemia model). Western blot and immunoprecipitation experiments revealed that overexpression of ITGB5 resulted in elevated integrin alphavbeta5 phosphorylation, followed by activation of Src kinase and signal transducer and activator of transcription 3 (STAT3). The specificity of ITGB5-dependent Src kinase and STAT3 phosphor-ylation was confirmed using function-blocking antibodies. Analysis of STAT3 target gene transcription revealed elevated mRNA and protein expression of the angiogenic chemokines IL8 and MCP1 in EPC-ITGB5, and significantly elevated IL8 and MCP1 protein levels in the conditioned medium (CdM) from EPC-ITGB5 were confirmed using quantitative ELISA. Moreover, CdM from EPC-ITGB5 enhanced the sprouting of co-incubated human umbilical vein endothelial cells (HUVEC) in a STAT3-dependent manner. Taken together, our findings suggest an important role for the cytoplasmic protein kinase Src in linking alphavbeta5 integrin to STAT3-dependent gene expression and angiogenesis. This pathway deserves further investigation as a possible means for (therapeutically) enhancing the paracrine potency of EPC.