Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 283, Issue 2, Pages H750-H759Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00029.2002
Keywords
native low-density lipoprotein; minimally oxidized low-density lipoprotein; smooth muscle cells; superoxide anion; confocal microscopy; hydroethidine
Funding
- NHLBI NIH HHS [HL 61414] Funding Source: Medline
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Low-density lipoprotein (LDL) and its oxidized derivatives are hypothesized to impair vascular function by increasing superoxide anion (O-2(-).). To investigate mechanisms in situ, isolated carotid arteries were incubated with native LDL (nLDL) or minimally oxidized LDL (mmLDL). With the use of en face fluorescent confocal microscopy and hydroethidine, an oxidant-sensitive fluorescent probe, we found that nLDL increased O-2(-). in vascular endothelium greater than fourfold by an N-omega-nitro-L-arginine methyl ester (L-NAME) inhibitable mechanism. In contrast, mmLDL increased O-2(-). in vascular endothelium greater than eightfold by mechanisms that were partially inhibited by L-NAME and allopurinol and essentially ablated by diphenyleneiodium. These data indicate that both nLDL and mmLDL uncouple endothelial nitric oxide synthase (eNOS) activity and that mmLDL also activates xanthine oxidase and NADPH oxidoreductase to induce greater increases in O-2(-). generation than nLDL. Western analysis revealed that both lipoproteins inhibited A-23187-stimulated association of heat shock protein 90 (HSP90) with eNOS without inhibiting phosphorylation of eNOS at serine-1179 (phospho-eNOS), an immunological index of electron flow through the enzyme. As HSP90 mediates the balance of .NO and O-2(-). generation by eNOS, these data provide new insight into the mechanisms by which oxidative stress, induced by nLDL and mmLDL, uncouple eNOS activity to increase endothelial O-2(-). generation.
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