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  • Ovid Technologies (Wolters Kluwer Health)  (4)
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  • Ovid Technologies (Wolters Kluwer Health)  (4)
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  • 1
    Online Resource
    Online Resource
    Atomic Level Dissection of the Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) Homophilic Binding Interface: Implications for Endothelial Cell Barrier Function
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. 2 ( 2022-02), p. 193-204
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. 2 ( 2022-02), p. 193-204
    Abstract: PECAM-1 (platelet endothelial cell adhesion molecule 1) is a 130 kDa member of the immunoglobulin (Ig) gene superfamily that is expressed on the surfaces of platelets and leukocytes and concentrated at the intercellular junctions of confluent endothelial cell monolayers. PECAM-1 Ig domains 1 and 2 (IgD1 and IgD2) engage in homophilic interactions that support a host of vascular functions, including support of leukocyte transendothelial migration and the maintenance of endothelial junctional integrity. The recently solved crystal structure of PECAM-1 IgD1 and IgD2 revealed a number of intermolecular interfaces predicted to play important roles in stabilizing PECAM-1/PECAM-1 homophilic interactions and in formation and maintenance of endothelial cell-cell contacts. We sought to determine whether the protein interfaces implicated in the crystal structure reflect physiologically important interactions. Approach and Results: We assessed the impact of single amino acid substitutions at the interfaces between opposing PECAM-1 molecules on homophilic binding and endothelial cell function. Substitution of key residues within the IgD1-IgD1 and IgD1-IgD2 interfaces but not those within the smaller IgD2-IgD2 interface, markedly disrupted PECAM-1 homophilic binding and its downstream effector functions, including the ability of PECAM-1 to localize at endothelial cell-cell borders, mediate the formation of endothelial tubes, and restore endothelial barrier integrity. Conclusions: Taken together, these results validate the recently described PECAM-1 IgD1/IgD2 crystal structure by demonstrating that specific residues visualized within the IgD1-IgD1 and IgD1-IgD2 interfaces of opposing molecules in the crystal are required for functionally important homophilic interactions. This information can now be exploited to modulate functions of PECAM-1 in vivo.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.121.316668
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1494427-3
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  • 2
    Online Resource
    Online Resource
    Geographic Variations in In‐Hospital Mortality and Use of Percutaneous Coronary Intervention Following Acute Myocardial Infarction in China: A Nationwide Cross‐Sectional Analysis
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of the American Heart Association Vol. 7, No. 8 ( 2018-04-17)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. 8 ( 2018-04-17)
    Abstract: Prevalence of acute myocardial infarction ( AMI ) is increasing in China, and AMI has become a major cause of mortality; however, information is very limited about the nationwide geographic and hospital variation in in‐hospital mortality ( IHM ) and the use of percutaneous coronary intervention ( PCI ) after AMI . Methods and Results From the Nationwide Hospital Discharge Database of China, we identified 242 866 adult admissions with AMI in 2015 from 1055 tertiary hospitals. We used multivariable logistic regressions to analyze the associations between geographic or hospital characteristics with IHM or PCI use. The national IHM rate was 4.71% (95% confidence interval, 4.62–4.79%). There was a greater risk of mortality in the Northeast (odds ratio [ OR ]: 1.86), West ( OR : 1.73), South ( OR : 1.32), and North ( OR : 1.14) regions than in the East region of China. Non–teaching hospitals ( OR : 1.18) and tertiary level B hospitals ( OR : 1.06) were associated with higher IHM rates. The national PCI use rate was 45.3% (95% confidence interval, 45.1–45.5%). Compared with the East region of China, PCI use was lower in the Northeast ( OR : 0.50), West ( OR : 0.64), North ( OR : 0.84), and South ( OR : 0.88) regions. Non–teaching hospitals ( OR : 0.83) and tertiary level B hospitals ( OR : 0.55) were also associated with lower usage rates. There was a significant negative correlation between IHM and PCI use ( r =−0.955), and IHM rates for patients with and without PCI both differed by geographic regions. Conclusions There were significant differences in IHM and PCI use among China's tertiary hospitals, linked to both geographic and hospital characteristics. More targeted intervention at national and regional levels is needed to improve access to effective health technologies and, eventually, outcomes following AMI .
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.117.008131
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2653953-6
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  • 3
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    Online Resource
    Abstract 14235: Hepatocyte Tissue Plasminogen Activator Limits Very-Low-Density Lipoprotein Production via Inhibiting ApoB-Microsomal Transfer Protein Interaction and ApoB Lipidation
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Lower plasma tissue plasminogen activator (tPA), a key fibrinolytic enzyme, is associated with higher atherogenic cholesterol levels in humans, but the mechanism is unknown. Hepatocyte (HC) is the factory producing atherogenic apoB lipoproteins, also a major source of basal plasma tPA. Our hypothesis is that tPA limits apoB-VLDL production in HCs.Silencing tPA in HCs using AAV8-H1-sh-tPA in Ldlr -/- mice leads to increased plasma cholesterol, triglyceride, apoB, and exacerbated atherosclerosis compared with scramble-silenced controls. Fractionation of plasma lipoproteins by FPLC or ultracentrifugation shows increased cholesterol and apoB in VLDL and LDL fractions. Inhibiting VLDL hydrolysis by P407 leads to a faster plasma triglyceride-rising rate in HC-tPA-silenced wild type mice, suggesting higher hepatic VLDL production. In a pulse-chase assay, tPA-silenced human primary HC has higher apoB-associated radioactivity in cell medium and lysate, suggesting increased apoB production.Adequate apoB lipidation is required for its secretion. By electronic microscopy, the distribution of VLDL shifts to a larger diameter in plasma VLDL isolated from HC-tPA-silenced Ldlr -/- mice, suggesting higher lipid contents in VLDL. The endoplasmic reticulum (ER)-associated apoB is higher in tPA-silenced vs. control HCs, more prominent in the less denser density fractions. As density and lipidation are inversely related, these findings are consistent with the hypothesis that tPA limits apoB lipidation in ER. MTP is an ER chaperone incorporating neutral lipids onto apoB in HC. The tPA-silenced human primary HC has higher neutral lipid transfer activity than controls, despite similar MTP protein levels. Moreover, higher apoB is in the anti-MTP-precipitations from tPA-silenced vs. control HCs, suggesting that silencing tPA increases apoB-MTP interaction. Proximity ligation and immunoprecipitation assays show tPA interacts with apoB in HC. Solid-phase binding assay and native gel reveal purified human tPA binds to LDL, but not to MTP. tPA competes with MTP in binding to LDL. Moreover, tPA inhibits MTP-mediated neutral lipid transfer. These findings suggested tPA binds to apoB and inhibits MTP-dependent apoB lipidation and VLDL secretion.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.14235
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 4
    Online Resource
    Online Resource
    Antiendothelial αvβ3 Antibodies Are a Major Cause of Intracranial Bleeding in Fetal/Neonatal Alloimmune Thrombocytopenia
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. 8 ( 2016-08), p. 1517-1524
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 8 ( 2016-08), p. 1517-1524
    Abstract: Fetal/neonatal alloimmune thrombocytopenia is a severe bleeding disorder, which can result in intracranial hemorrhage (ICH), leading to death or neurological sequelae. In whites, maternal anti–human platelet antigen-1a (HPA-1a) antibodies are responsible for the majority of cases. No predictive factors for ICH are available to guide prophylactic treatment during pregnancy. In this study, we investigated antibodies from mothers with ICH-positive fetal/neonatal alloimmune thrombocytopenia and with ICH-negative fetal/neonatal alloimmune thrombocytopenia to identify serological and functional differences between the groups. Approach and Results— In an antigen capture assay, we observed a stronger binding of +ICH antibodies to endothelial cell (EC)–derived αvβ3. By absorption experiments, we subsequently identified anti–HPA-1a antibodies of anti-αvβ3 specificity in the +ICH but not in the −ICH cohort. Only the anti–αvβ3 subtype, but not the anti–β3 subtype, induced EC apoptosis of HPA-1a–positive ECs by caspase-3/7 activation, and mediated by reactive oxygen species. In addition, only the anti–αvβ3 subtype, but not the anti-β3 subtype, interfered with EC adhesion to vitronectin and with EC tube formation. Conclusions— We conclude that the composition of the anti–HPA-1a antibody subtype(s) of the mother may determine whether ICH occurs. Analysis of anti–HPA-1a antibodies of the anti–αvβ3 subtype in maternal serum has potential in the diagnostic prediction of ICH development and may allow for modification of prophylactic treatment in fetal/neonatal alloimmune thrombocytopenia.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.116.307281
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1494427-3
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