title: ATP depletion in macrophages in the core of advanced rabbit atherosclerotic plaques in vivo.
abstract: 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.
authors.affiliation: Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Bruna Stråket 16, SE-413 45 Göteborg, Sweden.
authors.forename: Olli
authors.initials: O
authors.lastname: Leppänen
authors.forename: Tom
authors.initials: T
authors.lastname: Björnheden
authors.forename: Margareta
authors.initials: M
authors.lastname: Evaldsson
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Olov
authors.initials: O
authors.lastname: Wiklund
authors.forename: Max
authors.initials: M
authors.lastname: Levin
mesh_terms: 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
chemical_list: D019344:Lactic Acid; D000255:Adenosine Triphosphate; D006003:Glycogen; D008156:Luciferases; D005947:Glucose