The Effects of Lysophosphatidic Acid in Atherosclerotic Lesion

doi:10.3969/j.issn.1673-5765.2018.12.009

Abstract

Abstract:

Atherosclerosis is a severe and chronic inflammatory arterial disease that can lead to coronary heart disease, ischemic stroke and etc. Lysophosphatidic acid (LPA) plays a crucial role in the progression of atherosclerotic lesion by acting on endothelial cells, vascular smooth muscle cells, monocytes/macrophages, fibroblasts, dendritic cells, T-lymphocytes and platelets, which promotes atherosclerosis and thrombosis. Studies on the effects and pathophysiologic mechanisms of LPA in the atherosclerosis can contribute to find potential drugs and prevention measures for anti-atherosclerosis.

Key words: Lysophosphatidic acid; Atherosclerosis; Thrombosis; Endothelial cell

摘要：

动脉粥样硬化是一种严重的慢性动脉炎症性疾病，可以引起冠状动脉粥样硬化性心脏病和缺血性卒中等疾病。溶血磷脂酸在动脉粥样硬化的发生发展过程中起着至关重要的作用，它通过对血管内皮细胞、血管平滑肌细胞、单核-巨噬细胞、成纤维细胞、树突状细胞、T淋巴细胞及血小板等发挥作用促进动脉粥样硬化和血栓形成。探讨溶血磷脂酸在动脉粥样硬化发展中的作用和相关病理生理机制有助于探索抗动脉粥样硬化的潜在药物和干预措施。

关键词: 溶血磷脂酸; 动脉粥样硬化; 血栓形成; 内皮细胞

ZHANG Jian-Ping, LI Ya-Feng, GUO Geng. The Effects of Lysophosphatidic Acid in Atherosclerotic Lesion[J]. Chinese Journal of Stroke, 2018, 13(12): 1277-1281.

张建平, 李亚峰, 郭庚. 溶血磷脂酸在动脉粥样硬化病变中的作用[J]. 中国卒中杂志, 2018, 13(12): 1277-1281.

References

[1] SIESS W，ZANGL K J，ESSLER M，et al.

Lysophosphatidic acid mediates the rapid activation

of platelets and endothelial cells by mildly oxidized

low density lipoprotein and accumulates in human

atherosclerotic lesions[J]. Proc Natl Acad Sci USA，

1999，96（12）：6931-6936.

[2] CUI M Z. Lysophosphatidic acid effects on

atherosclerosis and thrombosis[J]. Clin Lipidol，2011，

6（4）：413-426.

[3] CHUN J，HLA T，LYNCH K R，et al. International

Union of Basic and Clinical Pharmacology. LXXVIII.

Lysophospholipid receptor nomenclature[J].

Pharmacol Rev，2010，62（4）：579-587.

[4] TOKUMURA A，MAJIMA E，KARIYA Y，et al.

Identification of human plasma lysophospholipase

D，a lysophosphatidic acid-producing enzyme，as

autotaxin，a multifunctional phosphodiesterase[J]. J

Biol Chem，2002，277（42）：39 436-39 442.

[5] GIERSE J，THORARENSEN A，BELTEY K，et al.

A novel autotaxin inhibitor reduces lysophosphatidic

acid levels in plasma and the site of inflammation[J].

J Pharmacol Exp Ther，2010，334（1）：310-317.

[6] FOURCADE O，SIMON M F，VIODÉ C，et al.

Secretory phospholipase A2 generates the novel

lipid mediator lysophosphatidic acid in membrane

microvesicles shed from activated cells[J]. Cell，1995，

80（6）：919-927.

[7] SONODA H，AOKI J，HIRAMATSU T，et al. A

novel phosphatidic acid-selective phospholipase A1

that produces lysophosphatidic acid[J]. J Biol Chem，

2002，277（37）：34 254-34 263.

[8] NAVAB M，CHATTOPADHYAY A，HOUGH

G，et al. Source and role of intestinally derived

lysophosphatidic acid in dyslipidemia and

atherosclerosis[J]. J Lipid Res，2015，56（4）：871-

887.

[9] AKHTAR S，HARTMANN P，KARSHOVSKA

E，et al. Endothelial Hypoxia-Inducible Factor-1α

Promotes Atherosclerosis and Monocyte Recruitment

by Upregulating MicroRNA-19a[J]. Hypertension，

2015，66（6）：1220-1226.

[10] LI Y F，LI R S，SAMUEL S B，et al.

Lysophospholipids and their G protein-coupled

receptors in atherosclerosis[J]. Front Biosci

（Landmark Ed），2016，21（1）：70-88.

[11] SMYTH S S，MUELLER P，YANG F，et al. Arguing

the case for the autotaxin-lysophosphatidic acidlipid

phosphate phosphatase 3-signaling nexus in the

development and complications of atherosclerosis[J].

Arterioscler Thromb Vasc Biol，2014，34（3）：479-

486.

[12] VAN NIEUW AMERONGEN G P，VERMEER M

A，VAN HINSBERGH V W. Role of RhoA and Rho

kinase in lysophosphatidic acid-induced endothelial

barrier dysfunction[J/OL]. Arterioscler Thromb

Vasc Biol，2000，20（12）：E127-E133. https：//www.

ahajournals.org/doi/abs/10.1161/01.atv.20.12.e127.

[13] BUSNELLI M，MANZINI S，PAROLINI

C，et al. Lipid phosphate phosphatase 3 in

vascular pathophysiology[J/OL]. Atherosclerosis，

2018，271：156-165. https：//doi.org/10.1016/

j.atherosclerosis.2018.02.025.

[14] WU C，HUANG R T，KUO C H，et al.

Mechanosensitive PPAP2B Regulates Endothelial

Responses to Atherorelevant Hemodynamic

Forces[J/OL]. Circ Res，2015，117（4）：e41-e53.

https：//www.ahajournals.org/doi/10.1161/

CIRCRESAHA.117.306457.

[15] TOUAT-HAMICI Z，WEIDMANN H，BLUM Y，et

al. Role of lipid phosphate phosphatase 3 in human

aortic endothelial cell function[J]. Cardiovasc Res，

2016，112（3）：702-713.

[16] ALDI S，MATIC L P，HAMM G，et al. Integrated

Human evaluation of the lysophosphatidic

acid pathway as a novel therapeutic target in

atherosclerosis[J/OL]. Mol Ther Methods Clin

Dev，2018，10：17-28. https：//doi.org/10.1016/

j.omtm.2018.05.003.

[17] SCHOBER A，SIESS W. Lysophosphatidic acid in

atherosclerotic diseases[J]. Br J Pharmacol，2012，

167（3）：465-482.

[18] HAYASHI K，TAKAHASHI M，NISHIDA W，et al.

Phenotypic modulation of vascular smooth muscle

cells induced by unsaturated lysophosphatidic

acids[J]. Circ Res，2001，89（3）：251-258.

[19] WU D D，ZHANG F，HAO F，et al. Matricellular

protein Cyr61 bridges lysophosphatidic acid and

integrin pathways leading to cell migration[J]. J Biol Chem，2014，289（9）：5774-5783.

[20] HAO F，ZHANG F，WU D D，et al.

Lysophosphatidic acid-induced vascular neointimal

formation in mouse carotid arteries is mediated

by the matricellular protein CCN1/Cyr61[J]. Am J

Physiol Cell Physiol，2016，311（6）：975-984.

[21] HAO F，TAN M，WU D D，et al. LPA induces IL-6

secretion from aortic smooth muscle cells via an

LPA1-regulated，PKC-dependent，and p38alphamediated

pathway[J]. Am J Physiol Heart Circ

Physiol，2010，298（3）：974-983.

[22] GUO H，MAKAROVA N，CHENG Y，et al. The

early- and late stages in phenotypic modulation of

vascular smooth muscle cells：differential roles for

lysophosphatidic acid[J]. Biochim Biophys Acta，

2008，1781（9）：571-581.

[23] LLODRÁ J，ANGELI V，LIU J，et al. Emigration

of monocyte-derived cells from atherosclerotic

lesions characterizes regressive，but not progressive，

plaques[J]. Proc Natl Acad Sci U S A，2004，101（32）：

11 779-11 784.

[24] RAY R，RAI V. Lysophosphatidic acid converts

monocytes into macrophages in both mice and

humans[J]. Blood，2017，129（9）：1177-1183.

[25] AN D，HAO F，ZHANG F，et al. CD14 is a

key mediator of both lysophosphatidic acid

and lipopolysaccharide induction of foam cell

formation[J]. J Biol Chem，2017，292（35）：14 391-

14 400.

[26] HOWELL K W，MENG X，FULLERTON D A，et

al. Toll-like receptor 4 mediates oxidized LDLinduced

macrophage differentiation to foam cells[J/

OL]. J Surg Res，2011，171（1）：e27-e31. https：//doi.

org/10.1016/j.jss.2011.06.033.

[27] YANG B，ZHOU Z，LI X，et al. The effect of

lysophosphatidic acid on Toll-like receptor 4

expression and the nuclear factor-κB signaling

pathway in THP-1 cells[J]. Mol Cell Biochem，2016，

422（1-2）：41-49.

[28] ZHENG H，FU Y，HUANG Y，et al. mTOR

signaling promotes foam cell formation and inhibits

foam cell egress through suppressing the SIRT1

signaling pathway[J]. Mol Med Rep，2017，16（3）：

3315-3323.

[29] YUNG Y C，STODDARD N C，CHUN J. LPA

receptor signaling：pharmacology，physiology，and

pathophysiology[J]. J Lipid Res，2014，55（7）：1192-

1214.

[30] CHEN R，ROMAN J，GUO J，et al.

Lysophosphatidic acid modulates the activation of

human monocyte-derived dendritic cells[J]. Stem

Cells Dev，2006，15（6）：797-804.

[31] BAI Z，CAI L，UMEMOTO E，et al. Constitutive

lymphocyte transmigration across the basal lamina

of high endothelial venules is regulated by the

autotaxin/lysophosphatidic acid axis[J]. J Immunol，

2013，190（5）：2036-2048.

[32] NAKASAKI T，TANAKA T，OKUDAIRA S，et al.

Involvement of the lysophosphatidic acid-generating

enzyme autotaxin in lymphocyte-endothelial cell

interactions[J]. Am J Pathol，2008，173（5）：1566-

1576.

[33] ROTHER E，BRANDL R，BAKER D L，et al.

Subtype-selective antagonists of lysophosphatidic

Acid receptors inhibit platelet activation triggered

by the lipid core of atherosclerotic plaques[J].

Circulation，2003，108（6）：741-747.