Академический Документы
Профессиональный Документы
Культура Документы
Review
1
Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan
2
Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo, Japan
Plasma levels of lipoproteins that contain apolipoprotein (apo) CⅢ predict coronary heart disease
(CHD), and associate with contributors to metabolic syndrome such as type 2 diabetes and hyper-
triglyceridemia. ApoCⅢ causes hypertriglyceridemia by inhibiting the catabolism and the clearance
of TG-rich lipoproteins (TLRs), and the association of apoCⅢ with CHD has been commonly
attributed to these properties; however, it has been untested whether apoCⅢ itself or in association
with lipoproteins directly affects atherogenic mechanisms in vascular cells. This review describes the
proatherogenic effect of apoCⅢ-containing lipoproteins. In brief, apoCⅢ-rich VLDL (VLDL CⅢ+)
increased the adhesion of human monocytes to vascular endothelial cells (ECs). ApoCⅢ alone also
increased monocyte adhesion to vascular ECs. Interestingly, apoCⅢ-rich HDL did not reduce the
adhesion of monocytes to vascular ECs, whereas HDL without apoCⅢ decreased their adhesion, sug-
gesting that apoCⅢ in HDL counteracts the anti-inflammatory property of HDL. ApoCⅢ alone as
well as VLDL CⅢ+ also activated vascular ECs through the activation of NF-κB, and induced the
recruitment of monocytes to vascular ECs. Moreover, apoCⅢ induced insulin resistance in vascular
ECs and caused endothelial dysfunction. These findings indicate that apoCⅢ in TLRs not only
modulates their metabolism, but also may directly contribute to the development of atherosclerosis
by activating the proinflammatory signal transduction of vascular cells. Here, we propose a novel role
for apoCⅢ that links dyslipidemia with atherosclerosis.
� � � ��������
�������
�������� ��������(�)
�������� ��������(�)
��� ��� ����������� ��������� �
�=� �=�
* ���������
��� ������
��� * ���α
* * ����Ⅲ
���
#
���
���κ� ����
#
���
����
��� ���
������
��������� � ���������
� Ⅲ+
�� −
� +
−
−
Ⅲ
�
�
���
���
�� �Ⅲ
�Ⅲ
�Ⅲ
�Ⅲ
�Ⅲ
��
������
�� � �
��
��
��
�
�
�
�
�
�
�
�
��
�
�
(������� ���� ��������� ��� ��) ���κ�
�������� �����������
Fig. 1. ApoCⅢ-rich lipoproteins modulate monocyte adhe- ����� ���βⅡ
sion to endothelial cells.
(This figure was drawn using data taken from reference No. 23, 26, and 27)
(A) Human peripheral monocytes were incubated in the presence
of the indicated lipoproteins (100 μg apoB/mL), apoCⅢ (100 μg/ Fig. 2. Schema depicting the mechanisms by which apoCⅢ
mL) or PBS (Control) for 8 hours, and static adhesion assays to activates monocytes and endothelial cells.
human umbilical vein endothelial cells (HUVECs) were carried
out. *p < 0.05 vs. Control, #p < 0.05 vs. VLDL CⅢ− or LDL CⅢ−. ApoCⅢ in TRLs activates PKC families and NF-κB, and increases
(B) Human peripheral monocytes were incubated with PBS (Con- the expression of integrins and adhesion molecules in monocytes
trol), HDL CⅢ+ or HDL CⅢ− (500 μg chol/mL) for 8 hours, and endothelial cells, causing their interaction. PC-PLC, phospha-
and static adhesion assays to HUVECs were carried out. *p < 0.05 tidylcholine-specific phospholipase C.
vs. Control.
VLDL particles (VLDL CⅢ+), but not VLDL parti- apoE decreased the proadhesive effect. Thus, apoCⅢ
cles without apoCⅢ increase the adhesion of mono- itself but not other apolipoproteins that commonly
cytes to vascular ECs; apoCⅢ protein itself caused this cluster with apoCⅢ on apoB lipoproteins or lipopro-
effect (Fig. 1A) 26), which was observed in a concentra- tein lipids mediate the enhanced monocyte adhesion
tion-dependent manner. Proadhesive concentrations to vascular ECs; however, further study is needed to
of apoCⅢ-containing lipoproteins, 50−100 μg apoB/ determine whether concomitant apoCⅠ, apoCⅡ, or
mL, are well within the range found in fasting plasma, apoE modifies the effects of apoCⅢ on monocyte
e.g. 50 μg apoB/mL in normolipidemic individuals, adhesion.
and >100 μg apoB/mL in hypertriglyceridemic indi- We then examined the mechanisms of apoCⅢ-
viduals or those with CHD, supporting their clinical induced monocyte activation. ApoCⅢ alone as well as
relevance. Some HDL preparations can inhibit the VLDL CⅢ+ activated β1-integrin in monocytes. Pro-
expression of integrins and adhesion molecules in leu- tein kinase C (PKC) plays an important role in several
kocytes and vascular ECs, and reduce their adhesive mechanisms that promote atherosclerosis, including
interaction 27), which is supposed to be one of anti- monocyte-endothelial interaction 28). We showed that
atherogenic properties of HDL. We examined the among PKCs, PKCα plays an important role in mono-
effect of apoCⅢ-rich HDL particles (HDL CⅢ+) on cyte β1-integrin activation by VLDL CⅢ+ or apoCⅢ
monocyte adhesion. HDL particles without apoCⅢ itself. We further identified pertussis toxin (PTX)-
(HDL CⅢ−) reduced monocyte adhesion to vascular sensitive G protein-coupled receptors and phosphati-
ECs in a concentration-dependent manner 26), while dylcholine-specific phospholipase C (PC-PLC) as key
HDL CⅢ+ did not (Fig . 1B). ApoCⅢ might have molecules that activate PKCα, NF-κB and β1-integ-
counteracted potentially atheroprotective actions of rin in monocytes (Fig. 2) 29). Our observations may
other HDL components. Our current data suggest a provide a role for apoCⅢ as a distinct contributor to
novel mechanism for HDL dysfunction induced by inflammation and atherosclerosis through monocyte
apoCⅢ. activation.
ApoCⅢ-containing lipoproteins also contain
other apolipoproteins, such as apoCⅠ, apoCⅡ, and
apoE, as well as various lipids; however, other apolipo- ApoCⅢ Activates Vascular Endothelial Cells
proteins or lipids extracted from apoCⅢ-containing The induction of adhesion molecules in vascular
VLDL did not increase monocyte adhesion. Antibodies ECs and the subsequent recruitment of circulating
against apoCⅢ but not against apoCⅠ, apoCⅡ or monocytes are proinflammatory events that promote
ApoCⅢ Induces Atherosclerosis 9
NF-κB in vascular cells, although our data suggest Apolipoprotein C-Ⅲ, metabolic syndrome, and risk of
receptors for apoCⅢ other than apoB/E receptor. Fur- coronary artery disease. J Lipid Res, 2003; 44:2374-2381
ther studies are also needed to elucidate the kinetics of 7) Cohn JS, Patterson BW, Uffelman KD, Davignon J,
Steiner G: Rate of production of plasma and very-low-
apoCⅢ-containing lipoproteins, and their atheroge- density lipoprotein (VLDL) apolipoprotein C-Ⅲ is
nicity on other types of cells, which will help to strongly related to the concentration and level of produc-
understand the overall atherogenicity of TRLs. tion of VLDL triglyceride in male subjects with different
Many previous studies have focused on the roles body weights and levels of insulin sensitivity. J Clin Endo-
of lipid moieties, such as oxidized lipids in atherogenic crinol Metab, 2004; 89:3949-3955
lipoproteins; however, our observations may provide 8) Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC,
novel insights into the role of apoCⅢ as a direct and Dallongeville J, Auwerx J: Fibrates downregulate apolipo-
distinct contributor to inflammation and atherosclero- protein C-Ⅲ expression independent of induction of per-
oxisomal acyl coenzyme A oxidase. A potential mecha-
sis. ApoCⅢ may be a new target for interventions, nism for the hypolipidemic action of fibrates. J Clin
particularly in subjects with insulin resistance, meta- Invest, 1995; 95:705-712
bolic syndrome and type 2 diabetes, because lowering 9) Lee SJ, Moye LA, Campos H, Williams GH, Sacks FM:
apoCⅢ not only improved the impaired metabolism Hypertriglyceridemia but not diabetes status is associated
of TRLs in these conditions, but also may directly with VLDL containing apolipoprotein CⅢ in patients
contribute to the prevention of atherosclerosis. with coronary heart disease. Atherosclerosis, 2003; 167:293-
302
10) Windler E, Havel RJ: Inhibitory effects of C apolipopro-
Acknowledgements teins from rats and humans on the uptake of triglyceride-
rich lipoproteins and their remnants by the perfused rat
We thank Makoto Harada for technical assistance. liver. J Lipid Res, 1985; 26:556-565
11) Quarfordt SH, Michalopoulos G, Schirmer B: The effect
of human C apolipoproteins on the in vitro hepatic metab-
Grant Support olism of triglyceride emulsions in the rat. J Biol Chem,
This study was supported by grants from the 1982; 257:14642-14647
Ministry of Education, Science and Technology 12) Clavey V, Lestavel-Delattre S, Copin C, Bard JM, Fruchart
JC: Modulation of lipoprotein B binding to the LDL
(10178102), ONO Medical Research Foundation, receptor by exogenous lipids and apolipoproteins CⅠ, CⅡ,
Takeda Science Foundation, Mitsukoshi Health and CⅢ, and E. Arterioscler Thromb Vasc Biol, 1995; 15:963-
Welfare Foundation, Uehara Memorial Foundation, 971
and a Sakakibara Memorial Research Grant from the 13) Sehayek E, Lewin-Velvert U, Chajek-Shaul T, Eisenberg S:
Japan Research Promotion Society for Cardiovascular Lipolysis exposes unreactive endogenous apolipoprotein
Diseases. E-3 in human and rat plasma very low density lipopro-
tein. J Clin Invest, 1991; 88:553-560
14) Wang CS, McConathy WJ, Kloer HU, Alaupovic P:
Modulation of lipoprotein lipase activity by apolipopro-
References teins. Effect of apolipoprotein C-Ⅲ. J Clin Invest, 1985;
1) Karathanasis SK: Apolipoprotein multigene family: tan- 75:384-390
dem organization of human apolipoprotein AⅠ, CⅢ, and 15) Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubin-
AⅣ genes. Proc Natl Acad Sci USA, 1985; 82:6374-6378 stein A, Wang-Iverson P, Norum R, Brown WV: Apolipo-
2) Jong MC, Hofker MH, Havekes LM: Role of ApoCs in protein B metabolism in subjects with deficiency of apoli-
lipoprotein metabolism: functional differences between poproteins CⅢ and AⅠ. Evidence that apolipoprotein CⅢ
ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc inhibits catabolism of triglyceride-rich lipoproteins by
Biol, 1999; 19:472-484 lipoprotein lipase in vivo. J Clin Invest, 1986; 78:1287-
3) Ooi EM, Barrett PH, Chan DC, Watts GF: Apolipopro- 1295
tein C-Ⅲ: understanding an emerging cardiovascular risk 16) Batal R, Tremblay M, Barrett PH, Jacques H, Fredenrich
factor. Clin Sci, 2008; 114:611-624 A, Mamer O, Davignon J, Cohn JS: Plasma kinetics of
4) Chen M, Breslow JL, Li W, Leff T: Transcriptional regula- apoC-Ⅲ and apoE in normolipidemic and hypertriglycer-
tion of the apoC-Ⅲ gene by insulin in diabetic mice: cor- idemic subjects. J Lipid Res, 2000; 41:706-718
relation with changes in plasma triglyceride levels. J Lipid 17) Ito Y, Azrolan N, O’Connell A, Walsh A, Breslow JL:
Res, 1994; 35:1918-1924 Hypertriglyceridemia as a result of human apo CⅢ gene
5) Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Mes- expression in transgenic mice. Science, 1990; 249:790-793
eck M, Dong HH: Foxo1 mediates insulin action on 18) Masucci-Magoulas L, Goldberg IJ, Bisgaier CL, Serajud-
apoC-Ⅲ and triglyceride metabolism. J Clin Invest, 2004; din H, Francone OL, Breslow JL, Tall AR: A mouse
114:1493-1503 model with features of familial combined hyperlipidemia.
6) Olivieri O, Bassi A, Stranieri C, Trabetti E, Martinelli N, Science, 1997; 275:391-394
Pizzolo F, Girelli D, Friso S, Pignatti PF, Corrocher R: 19) Maeda N, Li H, Lee D, Oliver P, Quarfordt SH, Osada J:
ApoCⅢ Induces Atherosclerosis 11
Targeted disruption of the apolipoprotein C-Ⅲ gene in vascular cell adhesion molecule-1 in vascular endothelial
mice results in hypotriglyceridemia and protection from cells and increases adhesion of monocytic cells. Circula-
postprandial hypertriglyceridemia. J Biol Chem, 1994; tion, 2006; 114:681-687
269:23610-23616 31) Campos H, Perlov D, Khoo C, Sacks FM: Distinct pat-
20) Alaupovic P, Mack WJ, Knight-Gibson C, Hodis HN: terns of lipoproteins with apoB defined by presence of
The role of triglyceride-rich lipoprotein families in the apoE or apoC-Ⅲ in hypercholesterolemia and hypertri-
progression of atherosclerotic lesions as determined by glyceridemia. J Lipid Res, 2001; 42:1239-1249
sequential coronary angiography from a controlled clini- 32) Kawakami A, Osaka M, Tani M, Azuma H, Sacks FM,
cal trial. Arterioscler Thromb Vasc Biol, 1997; 17:715-722 Shimokado K, Yoshida M: Apolipoprotein CⅢ links
21) Hodis HN: Triglyceride-rich lipoprotein remnant particles hyperlipidemia with vascular endothelial cell dysfunction.
and risk of atherosclerosis. Circulation, 1999; 99:2852- Circulation, 2008; 118:731-742
2854 33) Nakajima K, Saito T, Tamura A, Suzuki M, Nakano T,
22) Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Adachi M, Tanaka A, Tada N, Nakamura H, Campos E,
Stampfer MJ, Pfeffer MA, Braunwald E: VLDL, apolipo- et al: Cholesterol in remnant-like lipoproteins in human
proteins B, CⅢ, and E, and risk of recurrent coronary serum using monoclonal anti apo B-100 and anti apo A-Ⅰ
events in the Cholesterol and Recurrent Events (CARE) immunoaffinity mixed gels. Clin Chim Acta, 1993; 223:53-
trial. Circulation, 2000; 102:1886-1892 71
23) Lee SJ, Campos H, Moye LA, Sacks FM: LDL containing 34) Karpe F, Boquist S, Tang R, Bond GM, de Faire U, Ham-
apolipoprotein CⅢ is an independent risk factor for coro- sten A: Remnant lipoproteins are related to intima-media
nary events in diabetic patients. Arterioscler Thromb Vasc thickness of the carotid artery independently of LDL
Biol, 2003; 23:853-858 cholesterol and plasma triglycerides. J Lipid Res, 2001;
24) Onat A, Hergenç G, Sansoy V, Fobker M, Ceyhan K, 42:17-21
Toprak S, Assmann G: Apolipoprotein C-Ⅲ, a strong dis- 35) Nakada Y, Kurosawa H, Tohyama J, Inoue Y, Ikewaki K:
criminant of coronary risk in men and a determinant of Increased remnant lipoprotein in patients with coronary
the metabolic syndrome in both genders. Atherosclerosis, artery disease-evaluation utilizing a newly developed rem-
2003; 168:81-89 nant assay, remnant lipoproteins cholesterol homogenous
25) Zheng C, Khoo C, Ikewaki K, Sacks FM: Rapid turnover assay (RemL-C). J Atheroscler Thromb, 2007; 14:56-64
of apolipoprotein C-Ⅲ-containing triglyceride-rich lipo- 36) Marcoux C, Tremblay M, Nakajima K, Davignon J, Cohn
proteins contributing to the formation of LDL subfrac- JS: Characterization of remnant-like particles isolated
tions. J Lipid Res, 2007; 48:1190-1203 by immunoaffinity gel from the plasma of type Ⅲ and
26) Kawakami A, Aikawa M, Libby P, Alcaide P, Luscinskas type Ⅳ hyperlipoproteinemic patients. J Lipid Res, 1999;
FW, Sacks FM: Apolipoprotein CⅢ in apolipoprotein B 40:636-647
lipoproteins enhances the adhesion of human monocytic 37) Kawakami A, Yoshida M: Remnant lipoproteins and ath-
cells to endothelial cells. Circulation, 2006; 113:691-700 erogenesis. J Atheroscler Thromb, 2005; 12:73-76
27) Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, 38) Kawakami A, Tanaka A, Nakajima K, Shimokado K,
Navab M, Fogelman AM: Antiinflammatory properties of Yoshida M: Atorvastatin attenuates remnant lipopro-
HDL. Circ Res, 2004; 95:764-772 tein-induced monocyte adhesion to vascular endothelium
28) Rask-Madsen C, King GL: Proatherosclerotic mechanisms under flow conditions. Circ Res, 2002; 91:263-271
involving protein kinase C in diabetes and insulin resis- 39) Kawakami A, Tanaka A, Chiba T, Nakajima K, Shimo-
tance. Arterioscler Thromb Vasc Biol, 2005; 25:487-496 kado K, Yoshida M: Remnant lipoprotein-induced smooth
29) Kawakami A, Aikawa M, Nitta N, Yoshida M, Libby P, muscle cell proliferation involves epidermal growth factor
Sacks FM: Apolipoprotein CⅢ-induced THP-1 cell adhe- receptor transactivation. Circulation, 2003; 108:2679-2688
sion to endothelial cells involves pertussis toxin-sensitive 40) Kawakami A, Tani M, Chiba T, Yui K, Shinozaki S, Naka-
G-protein- and protein kinase C alpha-mediated nuclear jima K, Tanaka A, Shimokado K, Yoshida M: Pitavastatin
factor-kappaB activation. Arterioscler Thromb Vasc Biol, inhibits remnant lipoprotein-induced macrophage foam
2007; 27:219-225 cell formation through ApoB48 receptor-dependent mech-
30) Kawakami A, Aikawa M, Alcaide P, Luscinskas FW, Libby anism. Arterioscler Thromb Vasc Biol, 2005; 25:424-429
P, Sacks FM: Apolipoprotein CⅢ induces expression of