7-Ketocholesterol-induced lysosomal dysfunction exacerbates vascular smooth muscle cell calcification via oxidative stress

Autor:	Hiroshi Wachi, Fumiaki Sato, Takuya Azechi, Ryo Sudo
Rok vydání:	2015
Předmět:	Vascular smooth muscle Cell ATG5 Apoptosis Biology medicine.disease_cause Cathepsin D Muscle Smooth Vascular Cathepsin B Cell Line Genetics medicine Humans Vascular Calcification Ketocholesterols Dose-Response Relationship Drug Phosphorus Cell Biology Anatomy medicine.disease Cell biology Oxidative Stress medicine.anatomical_structure Gene Expression Regulation Lysosomes Oxidative stress Immunostaining Calcification
Zdroj:	Genes to Cells. 20:982-991
ISSN:	1356-9597
DOI:	10.1111/gtc.12301
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::68f11975e5b56c04cc7ca08919f1af41 https://doi.org/10.1111/gtc.12301 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.