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Thromb Haemost 2018; 118(06): 1021-1035
DOI: 10.1055/s-0038-1641750
Blood Cells, Inflammation and Infection
Schattauer GmbH Stuttgart

Apolipoprotein M Protects Lipopolysaccharide-Treated Mice from Death and Organ Injury

Makoto Kurano
1   Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
,
Koichi Tsuneyama
2   Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
,
Yuki Morimoto
2   Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
,
Tomo Shimizu
3   Research and Development Division, Tsukuba Research Institute, Sekisui Medical Co., Ltd., Ibaraki, Japan
,
Masahiro Jona
4   Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
,
Hidetoshi Kassai
5   Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
,
Kazuki Nakao
5   Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
,
Atsu Aiba
5   Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
,
Yutaka Yatomi
1   Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
› Author Affiliations Funding This work was supported by CREST from the JST/AMED, Leading Advanced Projects for medical innovation (LEAP) from AMED, a Grant-in-Aid for Scientific Research on Innovative Areas 15H05906 (Y.Y.), JSPS KAKENHI Grant Numbers 15K15378 and 16H06236 (M.K.) and MSD Life Science Foundation, Public Interest Incorporated Foundation (M.K.).
Further Information

Publication History

19 October 2017

05 March 2018

Publication Date:
18 April 2018 (online)

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Abstract

Objective High-density lipoprotein (HDL) has been epidemiologically shown to be associated with the outcome of sepsis. One potential mechanism is that HDL possesses pleiotropic effects, such as anti-apoptosis, some of which can be ascribed to sphingosine 1-phosphate (S1P) carried on HDL via apolipoprotein M (apoM). Therefore, the aim of this study was to elucidate the roles of apoM/S1P in the consequent lethal conditions of sepsis, such as multiple organ failure caused by severe inflammation and/or disseminated intravascular coagulation.

Methods and Results In mice treated with lipopolysaccharide (LPS), both plasma apoM levels and the expression of apoM in the liver and kidney were suppressed. The overexpression of apoM improved the survival rate and ameliorated the elevated plasma alanine aminotransferase (ALT) and creatinine levels, while the knockout or knockdown of apoM deteriorated these parameters in mice treated with LPS. Treatment with VPC23019, an antagonist against S1P receptor 1 and 3, or LY294002, a PI3K inhibitor, partially reversed these protective properties arising from the overexpression of apoM. The overexpression of apoM inhibited the elevation of plasma plasminogen activator inhibitor-1, restored the phosphorylation of Akt, and induced anti-apoptotic changes in the liver, kidney and heart.

Conclusion These results suggest that apoM possesses protective properties against LPS-induced organ injuries and could potentially be introduced as a novel therapy for the severe conditions that are consequent to sepsis.

Keywords

sphingosine 1-phosphate - apolipoprotein M - multiple organ failures - disseminated intravascular coagulation - lipopolysaccharide

Supplementary Material

 

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