Oxidation of LDL to a biologically active form by derivatives of nitric oxide and nitrite in the absence of superoxide. Dependence on pH and oxygen.
A key factor in atherogenesis is oxidation of LDL in the subendothelial space. In the normal vessel wall or in the thickened intima of diseased vessels, this space is rich in nitric oxide (NO.) released from endothelial cells, smooth muscle cells, and macrophages. To determine whether NO. has a role in LDL oxidation, we exposed human LDL to NO. under aerobic and anaerobic conditions and at acidic and neutral pH. Spectrophotometric detection of beta-carotene in the LDL was used as a marker for LDL oxidation. Depletion of beta-carotene was observed in LDL treated with NO. under aerobic conditions but not under anaerobic conditions. In contrast, treatment of LDL with sodium nitrite did not require oxygen for beta-carotene depletion, although depletion was increased when O2 was present. Furthermore, low pH greatly accelerated LDL oxidation by either NO. gas or by nitrite (NO2-). Depletion of beta-carotene corresponded with formation of conjugated dienes, increased susceptibility to further oxidation, and aggregation of apolipoprotein B-100, but did not increase electrophoretic mobility of LDL. Also, nitrite-oxidized LDL demonstrated biological properties similar to minimally oxidized LDL, including stimulation of monocyte adhesion and inhibition of lipopolysaccharide-induced neutrophil binding to endothelium. These results indicate that NO. under certain circumstances may contribute to oxidative modification of LDL and may have a role in atherogenesis.
Chang
G J
GJ
Department of Medicine, UCLA School of Medicine 90024-1679.
Woo
P
P
Honda
H M
HM
Ignarro
L J
LJ
Young
L
L
Berliner
J A
JA
Demer
L L
LL
D000818:Animals; D053299:Apolipoprotein B-100; D001053:Apolipoproteins / Q000032:analysis; D001055:Apolipoproteins B / Q000032:analysis; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D002338:Carotenoids / Q000037:antagonists & inhibitors; D002448:Cell Adhesion; D002460:Cell Line; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000494:pharmacology; D019207:beta Carotene
D053299:Apolipoprotein B-100; D001053:Apolipoproteins; D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D009573:Nitrites; D019207:beta Carotene; D013481:Superoxides; D002084:Butylated Hydroxytoluene; D009569:Nitric Oxide; D002338:Carotenoids; D013482:Superoxide Dismutase; D010100:Oxygen