Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

Christina Christoffersen; Hideru Obinata; Sunil B Kumaraswamy; Sylvain Galvani; Josefin Ahnström; Madhumati Sevvana; Claudia Egerer-Sieber; Yves A Muller; Timothy Hla; Lars Bo Nielsen; Björn Dahlbäck

doi:10.1073/pnas.1103187108

Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

Christina Christoffersen, Hideru Obinata, Sunil B Kumaraswamy, Sylvain Galvani, Josefin Ahnström, Madhumati Sevvana, Claudia Egerer-Sieber, Yves A Muller, Timothy Hla, Lars Bo Nielsen, Björn Dahlbäck

373 Citationer (Scopus)

Abstract

Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences USA (PNAS)
Vol/bind	108
Udgave nummer	23
Sider (fra-til)	9613-8
Antal sider	6
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.1103187108
Status	Udgivet - 7 jun. 2011

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10.1073/pnas.1103187108

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Christoffersen, C., Obinata, H., Kumaraswamy, S. B., Galvani, S., Ahnström, J., Sevvana, M., Egerer-Sieber, C., Muller, Y. A., Hla, T., Nielsen, L. B., & Dahlbäck, B. (2011). Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proceedings of the National Academy of Sciences USA (PNAS), 108(23), 9613-8. https://doi.org/10.1073/pnas.1103187108

Christoffersen, C, Obinata, H, Kumaraswamy, SB, Galvani, S, Ahnström, J, Sevvana, M, Egerer-Sieber, C, Muller, YA, Hla, T, Nielsen, LB & Dahlbäck, B 2011, 'Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M', Proceedings of the National Academy of Sciences USA (PNAS), bind 108, nr. 23, s. 9613-8. https://doi.org/10.1073/pnas.1103187108

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title = "Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M",

abstract = "Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-{\AA} structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL.",

keywords = "Animals, Apolipoproteins, Blotting, Western, Cells, Cultured, Crystallography, X-Ray, Endocytosis, Endothelial Cells, Endothelium, Vascular, Enzyme Activation, HEK293 Cells, Humans, Lipocalins, Lipoproteins, HDL, Lysophospholipids, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mitogen-Activated Protein Kinases, Models, Molecular, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt, Receptors, Lysosphingolipid, Sphingosine",

author = "Christina Christoffersen and Hideru Obinata and Kumaraswamy, {Sunil B} and Sylvain Galvani and Josefin Ahnstr{\"o}m and Madhumati Sevvana and Claudia Egerer-Sieber and Muller, {Yves A} and Timothy Hla and Nielsen, {Lars Bo} and Bj{\"o}rn Dahlb{\"a}ck",

year = "2011",

month = jun,

day = "7",

doi = "10.1073/pnas.1103187108",

language = "English",

volume = "108",

pages = "9613--8",

journal = "Proceedings of the National Academy of Sciences USA (PNAS)",

issn = "0027-8424",

publisher = "The National Academy of Sciences of the United States of America",

number = "23",

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TY - JOUR

T1 - Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

AU - Christoffersen, Christina

AU - Obinata, Hideru

AU - Kumaraswamy, Sunil B

AU - Galvani, Sylvain

AU - Ahnström, Josefin

AU - Sevvana, Madhumati

AU - Egerer-Sieber, Claudia

AU - Muller, Yves A

AU - Hla, Timothy

AU - Nielsen, Lars Bo

AU - Dahlbäck, Björn

PY - 2011/6/7

Y1 - 2011/6/7

N2 - Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL.

AB - Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL.

KW - Animals

KW - Apolipoproteins

KW - Blotting, Western

KW - Cells, Cultured

KW - Crystallography, X-Ray

KW - Endocytosis

KW - Endothelial Cells

KW - Endothelium, Vascular

KW - Enzyme Activation

KW - HEK293 Cells

KW - Humans

KW - Lipocalins

KW - Lipoproteins, HDL

KW - Lysophospholipids

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Mitogen-Activated Protein Kinases

KW - Models, Molecular

KW - Protein Binding

KW - Protein Conformation

KW - Protein Structure, Tertiary

KW - Proto-Oncogene Proteins c-akt

KW - Receptors, Lysosphingolipid

KW - Sphingosine

U2 - 10.1073/pnas.1103187108

DO - 10.1073/pnas.1103187108

M3 - Journal article

C2 - 21606363

SN - 0027-8424

VL - 108

SP - 9613

EP - 9618

JO - Proceedings of the National Academy of Sciences USA (PNAS)

JF - Proceedings of the National Academy of Sciences USA (PNAS)

IS - 23

ER -

Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M

Abstract

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