ATP depletion in macrophages in the core of advanced rabbit atherosclerotic plaques in vivo.
The cores of rabbit plaques in vivo are hypoxic, suggesting that ATP depletion due to an insufficient supply of oxygen and nutrients could contribute to macrophage death in atherosclerotic plaques. During hypoxia, however, macrophages maintain ATP levels by anaerobic glycolysis. To directly assess ATP and glucose metabolites in plaques in vivo, we used bioluminescence imaging to map the concentrations of ATP, glucose, glycogen, and lactate in normal and atherosclerotic rabbit aortas in vivo. Hypoxia was assessed with NITP (7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline). Normal aortas and plaques <500 microm thick were not hypoxic and had homogenous concentrations of energy metabolites. In plaques >500 microm thick, however, the cores were characterized by ATP depletion, low concentrations of glucose and glycogen, and a high concentration of lactate. A majority of ATP-depleted macrophages within the core were viable but severely hypoxic and glucose depleted. Hyperoxia in vitro reversed the ATP depletion in macrophages in viable areas of the core. Our findings suggest that ATP depletion contributes to the death of macrophages in atherosclerotic lesions and to the formation of a necrotic core.
Leppänen
Olli
O
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Bruna Stråket 16, SE-413 45 Göteborg, Sweden.
Björnheden
Tom
T
Evaldsson
Margareta
M
Borén
Jan
J
Wiklund
Olov
O
Levin
Max
M
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000473:pathology*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism; D008156:Luciferases; D008264:Macrophages / Q000378:metabolism*; D011817:Rabbits
D019344:Lactic Acid; D000255:Adenosine Triphosphate; D006003:Glycogen; D008156:Luciferases; D005947:Glucose