Endocardial endothelial dysfunction progressively disrupts initially anti then pro-thrombotic pathways in heart failure mice

Amanda Schoner, Christina Tyrrell, Melinda Wu, Jill Gelow, Alicia A. Hayes, Jonathan Lindner, Kent Thornburg, Wohaib Hasan

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    Abstract

    Objective An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes. Approach and results Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface. Conclusions CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.

    Original languageEnglish (US)
    Article numbere0142940
    JournalPLoS One
    Volume10
    Issue number11
    DOIs
    StatePublished - Nov 1 2015

    Fingerprint

    heart failure
    Heart Failure
    Thrombosis
    mice
    von Willebrand Factor
    blood coagulation factors
    thrombosis
    Protein C
    Endocardium
    Coagulants
    coagulants
    proteins
    incidence
    Incidence
    heart
    Ristocetin
    Echocardiography
    Thrombomodulin
    receptors
    Histology

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    Cite this

    Endocardial endothelial dysfunction progressively disrupts initially anti then pro-thrombotic pathways in heart failure mice. / Schoner, Amanda; Tyrrell, Christina; Wu, Melinda; Gelow, Jill; Hayes, Alicia A.; Lindner, Jonathan; Thornburg, Kent; Hasan, Wohaib.

    In: PLoS One, Vol. 10, No. 11, e0142940, 01.11.2015.

    Research output: Contribution to journalArticle

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    abstract = "Objective An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes. Approach and results Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface. Conclusions CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.",
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    T1 - Endocardial endothelial dysfunction progressively disrupts initially anti then pro-thrombotic pathways in heart failure mice

    AU - Schoner, Amanda

    AU - Tyrrell, Christina

    AU - Wu, Melinda

    AU - Gelow, Jill

    AU - Hayes, Alicia A.

    AU - Lindner, Jonathan

    AU - Thornburg, Kent

    AU - Hasan, Wohaib

    PY - 2015/11/1

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    N2 - Objective An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes. Approach and results Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface. Conclusions CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.

    AB - Objective An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes. Approach and results Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface. Conclusions CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.

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