Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries

Federico Moccetti, Eran Brown, Aris Xie, William Packwood, Qi Yue, Zaverio Ruggeri, Weihui Shentu, Junmei Chen, Jose A. López, Jonathan Lindner

    Research output: Contribution to journalArticle

    5 Citations (Scopus)

    Abstract

    Background: In the months after acute myocardial infarction (MI), risk for acute atherothrombotic events in nonculprit arteries increases several fold. Objectives: This study investigated whether sustained proinflammatory and prothrombotic endothelial alterations occur in remote vessels after MI. Methods: Wild-type mice, atherosclerotic mice with double knockout (DKO) of the low-density lipoprotein receptor and Apobec-1, and DKO mice treated with the Nox-inhibitor apocynin were studied at baseline and at 3 and 21 days after closed-chest MI. Ultrasound molecular imaging of P-selectin, vascular cell adhesion molecule (VCAM)-1, von Willebrand factor (VWF) A1-domain, and platelet GPIbα was performed. Intravital microscopy was used to characterize post-MI leukocyte and platelet recruitment in the remote microcirculation after MI. Results: Aortic molecular imaging for P-selectin, VCAM-1, VWF-A1, and platelets was increased several-fold (p < 0.01) 3 days post-MI for both wild-type and DKO mice. At 21 days, these changes resolved in wild-type mice but persisted in DKO mice. Signal for platelet adhesion was abolished 1 h after administration of ADAMTS13, which regulates VWF multimerization. In DKO and wild-type mice, apocynin significantly attenuated the post-MI increase for molecular targets, and platelet depletion significantly reduced P-selectin and VCAM-1 signal. On intravital microscopy, MI resulted in remote vessel leukocyte adhesion and platelet string or net complexes. On histology, high-risk inflammatory features in aortic plaque increased in DKO mice 21 days post-MI, which were completely prevented by apocynin. Conclusions: Acute MI stimulates a spectrum of changes in remote vessels, including up-regulation of endothelial inflammatory adhesion molecules and platelet-endothelial adhesion from endothelial-associated VWF multimers. These remote arterial alterations persist longer in the presence of hyperlipidemia, are associated with accelerated plaque growth and inflammation, and are attenuated by Nox inhibition.

    Original languageEnglish (US)
    Pages (from-to)1015-1026
    Number of pages12
    JournalJournal of the American College of Cardiology
    Volume72
    Issue number9
    DOIs
    StatePublished - Aug 28 2018

    Fingerprint

    Arteries
    Myocardial Infarction
    Blood Platelets
    Knockout Mice
    von Willebrand Factor
    P-Selectin
    Vascular Cell Adhesion Molecule-1
    Molecular Imaging
    Leukocytes
    LDL Receptors
    Microcirculation
    Hyperlipidemias
    Ultrasonography
    Histology
    Up-Regulation
    Thorax
    Inflammation
    Growth
    acetovanillone

    Keywords

    • adhesion molecules
    • myocardial infarction
    • platelets
    • von Willebrand factor

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries. / Moccetti, Federico; Brown, Eran; Xie, Aris; Packwood, William; Yue, Qi; Ruggeri, Zaverio; Shentu, Weihui; Chen, Junmei; López, Jose A.; Lindner, Jonathan.

    In: Journal of the American College of Cardiology, Vol. 72, No. 9, 28.08.2018, p. 1015-1026.

    Research output: Contribution to journalArticle

    Moccetti, Federico ; Brown, Eran ; Xie, Aris ; Packwood, William ; Yue, Qi ; Ruggeri, Zaverio ; Shentu, Weihui ; Chen, Junmei ; López, Jose A. ; Lindner, Jonathan. / Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries. In: Journal of the American College of Cardiology. 2018 ; Vol. 72, No. 9. pp. 1015-1026.
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    abstract = "Background: In the months after acute myocardial infarction (MI), risk for acute atherothrombotic events in nonculprit arteries increases several fold. Objectives: This study investigated whether sustained proinflammatory and prothrombotic endothelial alterations occur in remote vessels after MI. Methods: Wild-type mice, atherosclerotic mice with double knockout (DKO) of the low-density lipoprotein receptor and Apobec-1, and DKO mice treated with the Nox-inhibitor apocynin were studied at baseline and at 3 and 21 days after closed-chest MI. Ultrasound molecular imaging of P-selectin, vascular cell adhesion molecule (VCAM)-1, von Willebrand factor (VWF) A1-domain, and platelet GPIbα was performed. Intravital microscopy was used to characterize post-MI leukocyte and platelet recruitment in the remote microcirculation after MI. Results: Aortic molecular imaging for P-selectin, VCAM-1, VWF-A1, and platelets was increased several-fold (p < 0.01) 3 days post-MI for both wild-type and DKO mice. At 21 days, these changes resolved in wild-type mice but persisted in DKO mice. Signal for platelet adhesion was abolished 1 h after administration of ADAMTS13, which regulates VWF multimerization. In DKO and wild-type mice, apocynin significantly attenuated the post-MI increase for molecular targets, and platelet depletion significantly reduced P-selectin and VCAM-1 signal. On intravital microscopy, MI resulted in remote vessel leukocyte adhesion and platelet string or net complexes. On histology, high-risk inflammatory features in aortic plaque increased in DKO mice 21 days post-MI, which were completely prevented by apocynin. Conclusions: Acute MI stimulates a spectrum of changes in remote vessels, including up-regulation of endothelial inflammatory adhesion molecules and platelet-endothelial adhesion from endothelial-associated VWF multimers. These remote arterial alterations persist longer in the presence of hyperlipidemia, are associated with accelerated plaque growth and inflammation, and are attenuated by Nox inhibition.",
    keywords = "adhesion molecules, myocardial infarction, platelets, von Willebrand factor",
    author = "Federico Moccetti and Eran Brown and Aris Xie and William Packwood and Qi Yue and Zaverio Ruggeri and Weihui Shentu and Junmei Chen and L{\'o}pez, {Jose A.} and Jonathan Lindner",
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    AU - Moccetti, Federico

    AU - Brown, Eran

    AU - Xie, Aris

    AU - Packwood, William

    AU - Yue, Qi

    AU - Ruggeri, Zaverio

    AU - Shentu, Weihui

    AU - Chen, Junmei

    AU - López, Jose A.

    AU - Lindner, Jonathan

    PY - 2018/8/28

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    N2 - Background: In the months after acute myocardial infarction (MI), risk for acute atherothrombotic events in nonculprit arteries increases several fold. Objectives: This study investigated whether sustained proinflammatory and prothrombotic endothelial alterations occur in remote vessels after MI. Methods: Wild-type mice, atherosclerotic mice with double knockout (DKO) of the low-density lipoprotein receptor and Apobec-1, and DKO mice treated with the Nox-inhibitor apocynin were studied at baseline and at 3 and 21 days after closed-chest MI. Ultrasound molecular imaging of P-selectin, vascular cell adhesion molecule (VCAM)-1, von Willebrand factor (VWF) A1-domain, and platelet GPIbα was performed. Intravital microscopy was used to characterize post-MI leukocyte and platelet recruitment in the remote microcirculation after MI. Results: Aortic molecular imaging for P-selectin, VCAM-1, VWF-A1, and platelets was increased several-fold (p < 0.01) 3 days post-MI for both wild-type and DKO mice. At 21 days, these changes resolved in wild-type mice but persisted in DKO mice. Signal for platelet adhesion was abolished 1 h after administration of ADAMTS13, which regulates VWF multimerization. In DKO and wild-type mice, apocynin significantly attenuated the post-MI increase for molecular targets, and platelet depletion significantly reduced P-selectin and VCAM-1 signal. On intravital microscopy, MI resulted in remote vessel leukocyte adhesion and platelet string or net complexes. On histology, high-risk inflammatory features in aortic plaque increased in DKO mice 21 days post-MI, which were completely prevented by apocynin. Conclusions: Acute MI stimulates a spectrum of changes in remote vessels, including up-regulation of endothelial inflammatory adhesion molecules and platelet-endothelial adhesion from endothelial-associated VWF multimers. These remote arterial alterations persist longer in the presence of hyperlipidemia, are associated with accelerated plaque growth and inflammation, and are attenuated by Nox inhibition.

    AB - Background: In the months after acute myocardial infarction (MI), risk for acute atherothrombotic events in nonculprit arteries increases several fold. Objectives: This study investigated whether sustained proinflammatory and prothrombotic endothelial alterations occur in remote vessels after MI. Methods: Wild-type mice, atherosclerotic mice with double knockout (DKO) of the low-density lipoprotein receptor and Apobec-1, and DKO mice treated with the Nox-inhibitor apocynin were studied at baseline and at 3 and 21 days after closed-chest MI. Ultrasound molecular imaging of P-selectin, vascular cell adhesion molecule (VCAM)-1, von Willebrand factor (VWF) A1-domain, and platelet GPIbα was performed. Intravital microscopy was used to characterize post-MI leukocyte and platelet recruitment in the remote microcirculation after MI. Results: Aortic molecular imaging for P-selectin, VCAM-1, VWF-A1, and platelets was increased several-fold (p < 0.01) 3 days post-MI for both wild-type and DKO mice. At 21 days, these changes resolved in wild-type mice but persisted in DKO mice. Signal for platelet adhesion was abolished 1 h after administration of ADAMTS13, which regulates VWF multimerization. In DKO and wild-type mice, apocynin significantly attenuated the post-MI increase for molecular targets, and platelet depletion significantly reduced P-selectin and VCAM-1 signal. On intravital microscopy, MI resulted in remote vessel leukocyte adhesion and platelet string or net complexes. On histology, high-risk inflammatory features in aortic plaque increased in DKO mice 21 days post-MI, which were completely prevented by apocynin. Conclusions: Acute MI stimulates a spectrum of changes in remote vessels, including up-regulation of endothelial inflammatory adhesion molecules and platelet-endothelial adhesion from endothelial-associated VWF multimers. These remote arterial alterations persist longer in the presence of hyperlipidemia, are associated with accelerated plaque growth and inflammation, and are attenuated by Nox inhibition.

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    KW - platelets

    KW - von Willebrand factor

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