Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation

Yinyuan Ding, Linzhang Huang, Xunde Xian, Ivan S. Yuhanna, Catherine R. Wasser, Michael Frotscher, Chieko Mineo, Philip W. Shaul, Joachim Herz

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosisprone low-density lipoprotein receptor-deficient (Ldlr-/-) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule'1 (VCAM-1) and intercellular adhesion molecule'1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor kB (NF-kB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.

Original languageEnglish (US)
Article numberRA29
JournalScience Signaling
Volume9
Issue number419
DOIs
StatePublished - Mar 15 2016

Fingerprint

Macrophages
Cell adhesion
Endothelial cells
Cell Adhesion
Liver
Atherosclerosis
Leukocytes
Adhesion
Endothelial Cells
E-Selectin
Vascular Cell Adhesion Molecule-1
LDL Receptors
Nitric Oxide Synthase Type III
Intercellular Adhesion Molecule-1
Neurons
Glycoproteins
Blood
Hemostasis
Synaptic Transmission
Blood Vessels

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation. / Ding, Yinyuan; Huang, Linzhang; Xian, Xunde; Yuhanna, Ivan S.; Wasser, Catherine R.; Frotscher, Michael; Mineo, Chieko; Shaul, Philip W.; Herz, Joachim.

In: Science Signaling, Vol. 9, No. 419, RA29, 15.03.2016.

Research output: Contribution to journalArticle

Ding, Yinyuan ; Huang, Linzhang ; Xian, Xunde ; Yuhanna, Ivan S. ; Wasser, Catherine R. ; Frotscher, Michael ; Mineo, Chieko ; Shaul, Philip W. ; Herz, Joachim. / Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation. In: Science Signaling. 2016 ; Vol. 9, No. 419.
@article{3965892ea1104c208571061f1bafa84f,
title = "Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation",
abstract = "The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosisprone low-density lipoprotein receptor-deficient (Ldlr-/-) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule'1 (VCAM-1) and intercellular adhesion molecule'1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor kB (NF-kB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.",
author = "Yinyuan Ding and Linzhang Huang and Xunde Xian and Yuhanna, {Ivan S.} and Wasser, {Catherine R.} and Michael Frotscher and Chieko Mineo and Shaul, {Philip W.} and Joachim Herz",
year = "2016",
month = "3",
day = "15",
doi = "10.1126/scisignal.aad5578",
language = "English (US)",
volume = "9",
journal = "Science Signaling",
issn = "1937-9145",
publisher = "American Association for the Advancement of Science",
number = "419",

}

TY - JOUR

T1 - Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation

AU - Ding, Yinyuan

AU - Huang, Linzhang

AU - Xian, Xunde

AU - Yuhanna, Ivan S.

AU - Wasser, Catherine R.

AU - Frotscher, Michael

AU - Mineo, Chieko

AU - Shaul, Philip W.

AU - Herz, Joachim

PY - 2016/3/15

Y1 - 2016/3/15

N2 - The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosisprone low-density lipoprotein receptor-deficient (Ldlr-/-) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule'1 (VCAM-1) and intercellular adhesion molecule'1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor kB (NF-kB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.

AB - The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosisprone low-density lipoprotein receptor-deficient (Ldlr-/-) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin-deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule'1 (VCAM-1) and intercellular adhesion molecule'1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor kB (NF-kB) activity in an Apoer2-dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease.

UR - http://www.scopus.com/inward/record.url?scp=84962589802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962589802&partnerID=8YFLogxK

U2 - 10.1126/scisignal.aad5578

DO - 10.1126/scisignal.aad5578

M3 - Article

C2 - 26980442

AN - SCOPUS:84962589802

VL - 9

JO - Science Signaling

JF - Science Signaling

SN - 1937-9145

IS - 419

M1 - RA29

ER -