Atherosclerotic lesion progression changes lysophosphatidic acid homeostasis to favor its accumulation.
Am J Pathol
; 176(6): 3073-84, 2010 Jun.
Article
em En
| MEDLINE
| ID: mdl-20431029
ABSTRACT
Lysophosphatidic acid (LPA) accumulates in the central atheroma of human atherosclerotic plaques and is the primary platelet-activating lipid constituent of plaques. Here, we investigated the enzymatic regulation of LPA homeostasis in atherosclerotic lesions at various stages of disease progression. Atherosclerotic lesions were induced in carotid arteries of low-density lipoprotein receptor-deficient mice by semiconstrictive collar placement. At 2-week intervals after collar placement, lipids and RNA were extracted from the vessel segments carrying the plaque. Enzymatic-and liquid chromatography-mass spectrometry-based lipid profiling revealed progressive accumulation of LPA species in atherosclerotic tissue preceded by an increase in lysophosphatidylcholine, a precursor in LPA synthesis. Plaque expression of LPA-generating enzymes cytoplasmic phospholipase A(2)IVA (cPLA(2)IVA) and calcium-independent PLA(2)VIA (iPLA(2)VIA) was gradually increased, whereas that of the LPA-hydrolyzing enzyme LPA acyltransferase alpha was quenched. Increased expression of cPLA(2)IVA and iPLA(2)VIA in advanced lesions was confirmed by immunohistochemistry. Moreover, LPA receptors 1 and 2 were 50% decreased and sevenfold upregulated, respectively. Therefore, key proteins in LPA homeostasis are increasingly dysregulated in the plaque during atherogenesis, favoring intracellular LPA production. This might at least partly explain the observed progressive accumulation of this thrombogenic proinflammatory lipid in human and mouse plaques. Thus, intervention in the enzymatic LPA production may be an attractive measure to lower intraplaque LPA content, thereby reducing plaque progression and thrombogenicity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lisofosfolipídeos
/
Aterosclerose
/
Homeostase
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Am J Pathol
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Holanda