Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL

Sara Elsøe; Josefin Ahnström; Christina Christoffersen; Andrew N Hoofnagle; Peter Plomgaard; Jay W Heinecke; Christoph J Binder; Harry Björkbacka; Björn Dahlbäck; Lars Bo Nielsen

doi:10.1016/j.atherosclerosis.2011.11.031

Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL

Sara Elsøe, Josefin Ahnström, Christina Christoffersen, Andrew N Hoofnagle, Peter Plomgaard, Jay W Heinecke, Christoph J Binder, Harry Björkbacka, Björn Dahlbäck, Lars Bo Nielsen

70 Citations (Scopus)

Abstract

Objective: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. Methods and results: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ∼2-fold and ∼10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu ²⁺ or 2,2'-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. Conclusions: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM.

Original language	English
Journal	Atherosclerosis
Volume	221
Issue number	1
Pages (from-to)	91-7
Number of pages	7
ISSN	0021-9150
DOIs	https://doi.org/10.1016/j.atherosclerosis.2011.11.031
Publication status	Published - Mar 2012

Keywords

Amidines
Animals
Antioxidants
Apolipoproteins
Atherosclerosis
Binding Sites
Cholesterol, Dietary
Disease Models, Animal
Humans
Lipocalins
Lipoproteins, HDL
Lipoproteins, LDL
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myristic Acid
Oxidants
Oxidation-Reduction
Phospholipids
Receptors, LDL
Recombinant Proteins
Thiobarbituric Acid Reactive Substances
Time Factors

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10.1016/j.atherosclerosis.2011.11.031

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title = "Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL",

abstract = "Objective: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. Methods and results: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ∼2-fold and ∼10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu 2+ or 2,2'-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. Conclusions: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM.",

keywords = "Amidines, Animals, Antioxidants, Apolipoproteins, Atherosclerosis, Binding Sites, Cholesterol, Dietary, Disease Models, Animal, Humans, Lipocalins, Lipoproteins, HDL, Lipoproteins, LDL, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myristic Acid, Oxidants, Oxidation-Reduction, Phospholipids, Receptors, LDL, Recombinant Proteins, Thiobarbituric Acid Reactive Substances, Time Factors",

author = "Sara Els{\o}e and Josefin Ahnstr{\"o}m and Christina Christoffersen and Hoofnagle, {Andrew N} and Peter Plomgaard and Heinecke, {Jay W} and Binder, {Christoph J} and Harry Bj{\"o}rkbacka and Bj{\"o}rn Dahlb{\"a}ck and Nielsen, {Lars Bo}",

year = "2012",

month = mar,

doi = "10.1016/j.atherosclerosis.2011.11.031",

language = "English",

volume = "221",

pages = "91--7",

journal = "Atherosclerosis",

issn = "0021-9150",

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number = "1",

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TY - JOUR

T1 - Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL

AU - Elsøe, Sara

AU - Ahnström, Josefin

AU - Christoffersen, Christina

AU - Hoofnagle, Andrew N

AU - Plomgaard, Peter

AU - Heinecke, Jay W

AU - Binder, Christoph J

AU - Björkbacka, Harry

AU - Dahlbäck, Björn

AU - Nielsen, Lars Bo

PY - 2012/3

Y1 - 2012/3

N2 - Objective: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. Methods and results: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ∼2-fold and ∼10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu 2+ or 2,2'-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. Conclusions: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM.

AB - Objective: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. Methods and results: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ∼2-fold and ∼10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu 2+ or 2,2'-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. Conclusions: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM.

KW - Amidines

KW - Animals

KW - Antioxidants

KW - Apolipoproteins

KW - Atherosclerosis

KW - Binding Sites

KW - Cholesterol, Dietary

KW - Disease Models, Animal

KW - Humans

KW - Lipocalins

KW - Lipoproteins, HDL

KW - Lipoproteins, LDL

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Myristic Acid

KW - Oxidants

KW - Oxidation-Reduction

KW - Phospholipids

KW - Receptors, LDL

KW - Recombinant Proteins

KW - Thiobarbituric Acid Reactive Substances

KW - Time Factors

U2 - 10.1016/j.atherosclerosis.2011.11.031

DO - 10.1016/j.atherosclerosis.2011.11.031

M3 - Journal article

C2 - 22204862

SN - 0021-9150

VL - 221

SP - 91

EP - 97

JO - Atherosclerosis

JF - Atherosclerosis

IS - 1

ER -

Apolipoprotein M binds oxidized phospholipids and increases the antioxidant effect of HDL

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Keywords

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