7-Ketocholesterol-induced lysosomal dysfunction exacerbates vascular smooth muscle cell calcification via oxidative stress.
Genes Cells
; 20(12): 982-91, 2015 Dec.
Article
em En
| MEDLINE
| ID: mdl-26419830
ABSTRACT
Vascular calcification is known to reduce the elasticity of aorta. Several studies have suggested that autophagy-lysosomal pathway (ALP) in vascular smooth muscle cells (VSMCs) is associated with vascular calcification. A major component of oxidized low-density lipoproteins, 7-ketocholesterol (7-KC), has been reported to promote inorganic phosphorus (Pi)-induced vascular calcification and induce ALP. The aim of this study was to unravel the relationship between ALP and the progression of calcification by 7-KC. Calcification of human VSMCs was induced by Pi stimulation in the presence or absence of 7-KC. FACS analysis showed that 7-KC-induced apoptosis at a high concentration (30 µM), but not at a low concentration (15 µM). Interestingly, 7-KC promoted calcification in VSMCs regardless of apoptosis. Immunoblotting and immunostaining showed that 7-KC inhibits not only the fusion of autophagosomes and lysosomes but also causes a swell of lysosomes with the reduction of cathepsin B and D. Moreover, lysosomal protease inhibitors exacerbated the apoptosis-independent calcification by 7-KC although inhibition of autophagosome formation by Atg5 siRNA did not. Finally, the 7-KC-induced progression of calcification was alleviated by the treatment with antioxidant. Taken together, our data showed that 7-KC promotes VSMC calcification through lysosomal-dysfunction-dependent oxidative stress.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse Oxidativo
/
Calcificação Vascular
/
Cetocolesteróis
/
Lisossomos
/
Músculo Liso Vascular
Limite:
Humans
Idioma:
En
Revista:
Genes Cells
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Japão