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  • Ovid Technologies (Wolters Kluwer Health)  (14)
  • 1
    Online Resource
    Online Resource
    Drugs That Induce Repolarization Abnormalities Cause Bradycardia in Zebrafish
    Ovid Technologies (Wolters Kluwer Health) ; 2003
    In:  Circulation Vol. 107, No. 10 ( 2003-03-18), p. 1355-1358
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 107, No. 10 ( 2003-03-18), p. 1355-1358
    Abstract: Background— Drug-induced QT prolongation and torsades de pointes remain significant and often unpredictable clinical problems. Current in vitro preclinical assays are limited by biological simplicity, and in vivo models suffer from expense and low throughput. Methods and Results— During a screen for the effects of 100 small molecules on the heart rate of the zebrafish, Danio rerio , we found that drugs that cause QT prolongation in humans consistently caused bradycardia and AV block in the zebrafish. Of 23 such drugs tested, 18 were positive in this initial screen. Poor absorption explained 4 of 5 false-negative results, as demonstrated by microinjection. Overall, 22 of 23 compounds that cause repolarization abnormalities were positive in this assay. Antisense “knockdown” of the zebrafish KCNH2 ortholog yielded bradycardia in a dose dependent manner confirming the effects of reduction of repolarizing potassium current in this model. Classical drug-drug interactions between erythromycin and cisapride, as well as cimetidine and terfenadine, were also reproduced. Conclusion— This simple high-throughput assay is a promising addition to the repertoire of preclinical tests for drug-induced repolarization abnormalities. The genetic tractability of the zebrafish will allow the exploration of heritable modifiers of such drug effects.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000061912.88753.87
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2003
    detail.hit.zdb_id: 1466401-X
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  • 2
    Online Resource
    Online Resource
    Novel Chemical Suppressors of Long QT Syndrome Identified by an In Vivo Functional Screen
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Vol. 123, No. 1 ( 2011-01), p. 23-30
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 123, No. 1 ( 2011-01), p. 23-30
    Abstract: Genetic long QT (LQT) syndrome is a life-threatening disorder caused by mutations that result in prolongation of cardiac repolarization. Recent work has demonstrated that a zebrafish model of LQT syndrome faithfully recapitulates several features of human disease, including prolongation of ventricular action potential duration, spontaneous early afterdepolarizations, and 2:1 atrioventricular block in early stages of development. Because of their transparency, small size, and absorption of small molecules from their environment, zebrafish are amenable to high-throughput chemical screens. We describe a small-molecule screen using the zebrafish KCNH2 mutant breakdance to identify compounds that can rescue the LQT type 2 phenotype. Methods and Results— Zebrafish breakdance embryos were exposed to test compounds at 48 hours of development and scored for rescue of 2:1 atrioventricular block at 72 hours in a 96-well format. Only compounds that suppressed the LQT phenotype in 3 of 3 fish were considered hits. Screen compounds were obtained from commercially available small-molecule libraries (Prestwick and Chembridge). Initial hits were confirmed with dose-response testing and time-course studies. Optical mapping with the voltage-sensitive dye di-4 ANEPPS was performed to measure compound effects on cardiac action potential durations. Screening of 1200 small molecules resulted in the identification of flurandrenolide and 2-methoxy-N-(4-methylphenyl) benzamide (2-MMB) as compounds that reproducibly suppressed the LQT phenotype. Optical mapping confirmed that treatment with each compound caused shortening of ventricular action potential durations. Structure activity studies and steroid receptor knockdown suggest that flurandrenolide functions via the glucocorticoid signaling pathway. Conclusions— Using a zebrafish model of LQT type 2 syndrome in a high-throughput chemical screen, we have identified 2 compounds, flurandrenolide and the novel compound 2-MMB, as small molecules that rescue the zebrafish LQT type 2 syndrome by shortening the ventricular action potential duration. We provide evidence that flurandrenolide functions via the glucocorticoid receptor–mediated pathway. These 2 molecules and future discoveries from this screen should yield novel tools for the study of cardiac electrophysiology and may lead to novel therapeutics for human LQT patients.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.110.003731
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1466401-X
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  • 3
    Online Resource
    Online Resource
    Deciphering arterial identity through gene expression, genetics, and chemical biology
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Current Opinion in Hematology Vol. 15, No. 3 ( 2008-05), p. 221-227
    Details
    In: Current Opinion in Hematology, Ovid Technologies (Wolters Kluwer Health), Vol. 15, No. 3 ( 2008-05), p. 221-227
    Type of Medium: Online Resource
    ISSN: 1065-6251
    URL: Article
    DOI: 10.1097/MOH.0b013e3282f97daa
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 2026995-X
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  • 4
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    Online Resource
    Abstract 5566: Recovery of Erk Signaling Restores Defective Angiogenesis and Arteriogenesis in Synectin-Deficient Animals
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Vol. 118, No. suppl_18 ( 2008-10-28)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. suppl_18 ( 2008-10-28)
    Abstract: Background : Arterial morphogenesis is an important and poorly understood process. We have previously demonstrated that disruption of synectin gene expression in mice and zebrafish results in impaired arterial development and branching morphogenesis. Synectin null endothelial cells demonstrate reduced VEGF responsiveness in terms of migration, proliferation and differentiation and ERK-1/2 activation (Chittenden et al, Dev Cell 2006). Since ERK has been established as major participants in the regulation of cell growth and differentiation and Erk activation has been previously linked to arterial morphogenesis, we evaluated whether activation of Erk signaling in synectin disrupted mice and zebrafish as well as synectin KO arterial endothelial cells (ECs) would restore defective migration, arterial differentiation, angiogenesis and arteriogenesis. To stimulate ERK signaling we used partial inhibition of PI3-K activity to reduce Akt-dependent suppression of Raf1 activation or introduction of constitutively active ERK construct. Methods : In vitro studies were conducted with primary arterial ECs isolated from synectin wild type (WT) and knock out (KO) mice. In vivo studies were carried out in WT and synectin deficient mice and synectin knockdown zebrafish embryos. Results: Exposure of synectin −/− arterial EC to two selective PI3K inhibitors GS4898 or LY294002 in vitro restored ERK activation in a dose-dependent manner and returned cell migration and in vitro branching morphogenesis to wild type levels. Transduction of a constitutively active ERK construct in vitro or in a Matrigel model in vivo had similar effect. Systemic treatment of synectin −/− mice with GS4898 fully restored impaired angiogenesis and arterial morphogenesis in adult animals in the setting of hindlimb ischemia. Similar treatment nearly completely restored arterial development defects in zebrafish treated with a synectin morpholino. Conclusions: ERK activation plays a key role in arteriogenesis both in adult tissues and during embryonic development. Activation of compromised ERK-1/2 signaling may be a novel therapeutic intervention to stimulate arteriogenesis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.118.suppl_18.S_576-a
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1466401-X
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  • 5
    Online Resource
    Online Resource
    An Updated Definition of Stroke for the 21st Century : A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. 7 ( 2013-07), p. 2064-2089
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 7 ( 2013-07), p. 2064-2089
    Abstract: Despite the global impact and advances in understanding the pathophysiology of cerebrovascular diseases, the term “stroke” is not consistently defined in clinical practice, in clinical research, or in assessments of the public health. The classic definition is mainly clinical and does not account for advances in science and technology. The Stroke Council of the American Heart Association/American Stroke Association convened a writing group to develop an expert consensus document for an updated definition of stroke for the 21st century. Central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury. Central nervous system infarction occurs over a clinical spectrum: Ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms, while silent infarction by definition causes no known symptoms. Stroke also broadly includes intracerebral hemorrhage and subarachnoid hemorrhage. The updated definition of stroke incorporates clinical and tissue criteria and can be incorporated into practice, research, and assessments of the public health.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STR.0b013e318296aeca
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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  • 6
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    Online Resource
    Abstract 229: Protein Kinase D-1 Regulates CD36 Transcription and Arteriogenic Differentiation of Endothelial Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, No. suppl_1 ( 2013-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. suppl_1 ( 2013-05)
    Abstract: CD36 is a microvascular endothelial cell (MVEC) receptor mediating angiostatic activity of TSP-1 and related proteins. We previously reported that lysophosphatidic acid (LPA), a biologically active lipid signaling mediator, inhibited MVEC CD36 transcription via PKD-1 signaling. Moreover, CD36 transcriptional repression abolished endothelial cell responses to TSP-1 in vitro and in vivo . We now show with luciferase transfection assays that LPA exposure significantly suppressed CD36 promoter activity in MVEC. Co-exposure to class II HDAC inhibitors SAHA or TSA reversed the inhibition of promoter activity and restored transcription. HDAC7 knockdown by shRNA also attenuated LPA-suppressed CD36 promoter activity and mRNA levels. Mechanistically, FoxO1 was found to directly interact with putative FoxO1 binding sites (FHRE) in proximal promoter in vitro by avidin-biotin-conjugated DNA-binding assay, and in vivo by chromatin IP assay. Furthermore, FHRE mutations significantly attenuated the promoter activity. Western blots and immunofluorescence microscopy showed increased nuclear accumulation of PKD-1, FoxO1 and HADC7 after MVEC were exposed to LPA. Co-IP of nuclear extracts showed a physical interaction of HDAC7 with FoxO1 that was attenuated with PKD-1 knockdown. These data demonstrate that HDAC7 modulation by LPA receptor/PKD-1 signaling pathway represses FoxO1-mediated CD36 transcriptional activity. Additionally, angiogenic transcription profiling of endothelial cells revealed significantly increased mRNA expression of 17 angiogenic genes in response to LPA, including ephrin B2 expression that was confirmed by Western Blots. Transduction of constitutively active PKD-1 (PKD-CA) into EC also increased ephrin B2 expression. Functionally, PKD-CA overexpression promoted branching morphogenesis of arterial endothelial cells in a three-dimensional spheroid assay. The data indicate that PKD-1 is a potent angiogenic and arteriogenic kinase in EC by down-regulating CD36 transcription and promoting arteriogenesis. PKD-1-FoxO1-CD36 signaling axis may have potential as an important target in cardiovascular ischemia and malignant tumors.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.33.suppl_1.A229
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1494427-3
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  • 7
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    Online Resource
    Drug-Sensitized Zebrafish Screen Identifies Multiple Genes, Including GINS3 , as Regulators of Myocardial Repolarization
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Circulation Vol. 120, No. 7 ( 2009-08-18), p. 553-559
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 120, No. 7 ( 2009-08-18), p. 553-559
    Abstract: Background— Cardiac repolarization, the process by which cardiomyocytes return to their resting potential after each beat, is a highly regulated process that is critical for heart rhythm stability. Perturbations of cardiac repolarization increase the risk for life-threatening arrhythmias and sudden cardiac death. Although genetic studies of familial long-QT syndromes have uncovered several key genes in cardiac repolarization, the major heritable contribution to this trait remains unexplained. Identification of additional genes may lead to a better understanding of the underlying biology, aid in identification of patients at risk for sudden death, and potentially enable new treatments for susceptible individuals. Methods and Results— We extended and refined a zebrafish model of cardiac repolarization by using fluorescent reporters of transmembrane potential. We then conducted a drug-sensitized genetic screen in zebrafish, identifying 15 genes, including GINS3 , that affect cardiac repolarization. Testing these genes for human relevance in 2 concurrently completed genome-wide association studies revealed that the human GINS3 ortholog is located in the 16q21 locus, which is strongly associated with QT interval. Conclusions— This sensitized zebrafish screen identified 15 novel myocardial repolarization genes. Among these genes is GINS3 , the human ortholog of which is a major locus in 2 concurrent human genome-wide association studies of QT interval. These results reveal a novel network of genes that regulate cardiac repolarization.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.108.821082
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
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  • 8
    Online Resource
    Online Resource
    Systematizing Serendipity for Cardiovascular Drug Discovery
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Circulation Vol. 120, No. 3 ( 2009-07-21), p. 255-263
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 120, No. 3 ( 2009-07-21), p. 255-263
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.108.824177
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
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  • 9
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    Online Resource
    Role of Crosstalk Between Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Pathways in Artery–Vein Specification
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Research Vol. 103, No. 6 ( 2008-09-12), p. 573-579
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 103, No. 6 ( 2008-09-12), p. 573-579
    Abstract: Functional and structural differences between arteries and veins lie at the core of the circulatory system, both in health and disease. Therefore, understanding how artery and vein cell identities are established is a fundamental biological challenge with significant clinical implications. Molecular genetic studies in zebrafish and other vertebrates in the past decade have begun to reveal in detail the complex network of molecular pathways that specify artery and vein cell fates during embryonic development. Recently, a chemical genetic approach has revealed evidence that artery–vein specification is governed by cross talk between phosphoinositide 3-kinase and extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling in artery–vein specification. We discuss recent findings on the signaling pathways involved in artery–vein specification during zebrafish development and compare and contrast these results to those from mammalian systems. It is anticipated that the complementary approaches of genetics and chemical biology, involving a variety of model organisms and systems, will lead to a better understanding of artery–vein specification and possibly to novel therapeutic approaches to treat vascular diseases.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.108.180745
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1467838-X
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  • 10
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    Online Resource
    Further Observations on Postgastrectomy Steatorrhea : The Effect of High Carbohydrate Intake and of Hydrochloric Acid Administration on Fat Absorption
    Ovid Technologies (Wolters Kluwer Health) ; 1959
    In:  Annals of Surgery Vol. 150, No. 3 ( 1959-09), p. 517-528
    Details
    In: Annals of Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 150, No. 3 ( 1959-09), p. 517-528
    Type of Medium: Online Resource
    ISSN: 0003-4932
    URL: Article
    DOI: 10.1097/00000658-195909000-00015
    RVK:
    XA 23900
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1959
    detail.hit.zdb_id: 2002200-1
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