Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration.
Cell Metab
; 17(4): 549-61, 2013 Apr 02.
Article
em En
| MEDLINE
| ID: mdl-23562078
ABSTRACT
Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Colesterol
/
Macrófagos
/
Degeneração Macular
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Metab
Assunto da revista:
METABOLISMO
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos