Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes.
Circulation
; 117(10): 1310-7, 2008 Mar 11.
Article
em En
| MEDLINE
| ID: mdl-18268153
ABSTRACT
BACKGROUND:
The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-gamma (PI3Kgamma) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kgamma in the cardiovascular system suggest that PI3Kgamma plays a role in atherosclerosis. METHODS ANDRESULTS:
Here, we demonstrate that a specific PI3Kgamma inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E-deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor-deficient mice. Furthermore, PI3Kgamma levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor-deficient mice transplanted with wild-type or PI3Kgamma-deficient bone marrow demonstrated that functional PI3Kgamma in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kgamma activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization.CONCLUSIONS:
These data identify PI3Kgamma as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinoxalinas
/
Tiazolidinedionas
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Aterosclerose
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Inibidores de Fosfoinositídeo-3 Quinase
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Circulation
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
França