High glucose downregulates the number of caveolae in monocytes through oxidative stress from NADPH oxidase: implications for atherosclerosis.
Atherosclerosis, an inflammatory disease, is closely associated with hyperglycemia, major sign of diabetes mellitus. Caveolae are vesicular invaginations of the plasma membrane that mediate the intracellular transport of lipids such as cholesterol. We evaluated the relationship between the expression of caveolin-1 and the number of caveolae in macrophages under conditions of high glucose concentration. Increased superoxide production, induction of inducible nitric oxide synthase (iNOS), and decreased caveolin-1 were observed in a concentration-dependent manner in THP-1 derived macrophages with high glucose concentrations. Mannitol, used as an osmotic control, showed no effects. Furthermore, co-localization of the NADPH oxidase component, p47(phox), and caveolin was confirmed by confocal microscopy. An atomic force microscopy (AFM) study showed that high glucose concentrations reduced the number and size of the caveolae. The percentage of cells with fragmented DNA was increased in cells grown in hyperglycemic media. Taken together, high glucose concentrations suppress the levels of caveolin-1 expression and reduce the number of caveolae. This might be due to the actions of superoxide via the activation of NADPH oxidase by translocation of its component and uncoupling of induced iNOS in macrophages. Furthermore, the apoptosis of macrophages might occur with high glucose concentrations, leading to the spreading of lipids from macrophages into intracellular spaces in the vessel wall.
Hayashi
Toshio
T
Department of Geriatrics, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan. hayashi@med.nagoya-u.ac.jp
Juliet
Packiasamy A R
PA
Miyazaki
Asaka
A
Ignarro
Louis J
LJ
Iguchi
Akihisa
A
D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism / Q000648:ultrastructure*; D051242:Caveolin 1 / Q000032:analysis / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure*; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D019255:NADPH Oxidases / Q000032:analysis / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism
D051242:Caveolin 1; D013481:Superoxides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D005947:Glucose