Native and oxidized low-density lipoproteins modulate the vasoactive actions of soluble beta-amyloid peptides in rat aorta.
Cerebrovascular accumulation of Abeta (beta-amyloid) occurs in aging and AD (Alzheimer's disease). Hypercholesterolaemia, which is associated with raised plasma LDL (low-density lipoprotein), may predispose to AD. Soluble Abeta is found in the circulation and enhances vasoconstriction. Under conditions that may favour the formation of short Abeta oligomers, as opposed to more severe polymerization leading to Abeta fibrillogenesis, we investigated the influence of LDLs on the vasoactive actions of soluble Abeta. Thus the actions of Abeta40 and Abeta42 in combination with native or oxidized LDL on vasoconstriction to NA (noradrenaline) and vasodilatation to ACh (acetylcholine) were examined in rat aortic rings. LDL, particularly when oxidized, potentiated NA-induced constriction when combined with soluble Abeta40 and, especially, Abeta42. Soluble Abeta40 reduced relaxation induced by ACh, but Abeta42 was ineffective. Native and oxidized LDL also attenuated relaxation. Synergism occurred between oxidized LDL and Abeta with respect to ACh-induced relaxation, but not between native LDL and Abeta. We have shown for the first time that, under conditions that may result in Abeta oligomer formation, LDL, particularly when oxidized, modulates the vascular actions of soluble Abeta to extents greater than those reported previously for fibrillar Abeta preparations. Mechanisms whereby a treatable condition, namely hypercholesterolaemia, might contribute to the development of the cerebrovascular component of AD are indicated.
Smith
Christopher C T
CC
The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, UK. christopher.smith@ucl.ac.uk
Stanyer
Lee
L
Betteridge
D John
DJ
Cooper
Michael B
MB
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000682:Amyloid / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008077:Lipoproteins, LDL; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C099252:oxidized low density lipoprotein; D000109:Acetylcholine; D009638:Norepinephrine