Expression of type IIA secretory phospholipase A2 inhibits cholesteryl ester transfer protein activity in transgenic mice.
Arterioscler Thromb Vasc Biol
; 33(12): 2707-14, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-24115030
ABSTRACT
OBJECTIVE:
High circulating levels of group IIA secretory phospholipase A2 (sPLA2-IIA) activity and mass are independent cardiovascular risk factors. Therefore, inhibition of sPLA2-IIA may be a target for the treatment of atherosclerotic cardiovascular disease. The present study evaluated the effects of sPLA2-IIA inhibition with varespladib acid in a novel mouse model, human apolipoprotein B (apoB)/human cholesteryl ester transfer protein (CETP)/human sPLA2-IIA triple transgenic mice (TTT) fed a Western-type diet. APPROACH ANDRESULTS:
sPLA2-IIA expression increased atherosclerotic lesion formation in TTT compared with human apoB/human CETP double transgenic mice (P<0.01). Varespladib acid effectively inhibited plasma sPLA2-IIA activity. Surprisingly, however, administration of varespladib acid to TTT had no impact on atherosclerosis, which could be attributed to a proatherogenic plasma lipoprotein profile that appears in response to sPLA2-IIA inhibition because of increased plasma CETP activity. In the TTT model, sPLA2-IIA decreased CETP activity by reducing the acceptor properties of sPLA2-IIA-modified very low-density lipoproteins specifically because of a significantly lower apoE content. Increasing very low-density lipoprotein-apoE content by means of adenovirus-mediated gene transfer in sPLA2-IIA transgenic mice restored the acceptor properties for CETP.CONCLUSIONS:
These data show that in a humanized triple transgenic mouse model with hypercholesterolemia, sPLA2-IIA inhibition increases CETP activity via increasing the very low-density lipoprotein-apoE content, resulting in a proatherogenic lipoprotein profile.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Aorta
/
Doenças da Aorta
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Aterosclerose
/
Proteínas de Transferência de Ésteres de Colesterol
/
Fosfolipases A2 do Grupo II
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article