Oxidation of LDL by Myeloperoxidase and Reactive Nitrogen Species

Abstract

Abstract-Oxidative modification of low density lipoprotein (LDL) appears to play an important role in atherogenesis.Although the precise mechanisms of LDL oxidation in vivo are unknown, several lines of evidence implicate myeloperoxidase and reactive nitrogen species, in addition to ceruloplasmin and 15-lipoxygenase. Myeloperoxidase generates a number of reactive species, including hypochlorous acid, chloramines, tyrosyl radicals, and nitrogen dioxide. Key Words: low density lipoproteins Ⅲ myeloperoxidase Ⅲ reactive nitrogen species Ⅲ vitamin C Ⅲ vitamin E T he hypothesis that oxidative stress plays an important role in the pathogenesis of atherosclerosis has gained considerable support. Although there are many determinants in the development of an atherosclerotic lesion, substantial in vitro evidence links LDL oxidation to potentially atherogenic processes at the molecular and cellular level. 1-3 However, the in vivo mechanism(s) of the initiation and progression of LDL oxidation is presently unclear and is a topic of much research. The most relevant information concerning this mechanism has come from immunohistochemical and biochemical analyses of animal and human atherosclerotic lesions and lipoproteins extracted from these lesions. Ceruloplasmin, 15-lipoxygenase, myeloperoxidase (MPO), and inducible (in addition to endothelial) nitric oxide synthase (NOS) have been found in animal and human lesions and can cause or contribute to LDL oxidation in vitro. 2,4 -10 With respect to a role for ceruloplasmin in in vivo LDL oxidation, specific markers of metal ion-catalyzed protein damage are not elevated in early or intermediate lesions, in contrast to advanced lesions. 9,11 Immunohistochemical detection of aldehyde-modified LDL in human and animal lesions 12,13 also has been used as evidence for metal ionmediated oxidation; however, the specificity of antibodies raised against aldehyde-modified or copper-oxidized LDL has been questioned, because these can cross-react with LDL modified by hypochlorous acid (HOCl). 14 Therefore, it appears unlikely that ceruloplasmin and other sources of redoxactive metal ions contribute significantly to LDL oxidation in vivo during the early stages of atherosclerotic lesion development.The role of 15-lipoxygenase in LDL oxidation and atherogenesis is controversial, because the mechanism by which the intracellular enzyme "seeds" extracellular LDL with hydroperoxides is unclear. 15,16 Furthermore, there is limited evidence for the presence of 15-lipoxygenase-modified lipids in lesions, because only small increases in the S/R enantiomeric ratio of lipid hydro(pero)xides were detected. 17,18 Nevertheless, immunohistochemical studies have demonstrated the presence of 15-lipoxygenase in macrophage-rich regions of human and rabbit atherosclerotic lesions, 19,20 and epitopes of oxidized LDL colocalize with 15-lipoxygenase. 20 Interestingly, cholesterol-fed transgenic rabbits overexpressing the human 15-lipoxygenase gene in macrophages develop significantly less atherosclerosis than do the...

Inflammation in Atherosclerosis and Implications for Therapy

“…5 It is believed that oxidation of LDL may be modulated by nitric oxide (NO) and its products, as well as by myeloperoxidase and ceruloplasmin. 6,7 In one study, levels of oxidized LDL were significantly higher in patients with acute MI than in patients with angina or in controls, although lipid profiles did not differ among these groups. 8 In atherectomy specimens, the surface area containing macrophages that were positive for oxidized LDL was greater in patients with unstable angina than in those with stable angina.…”

Bioactive compounds and scavenging capacity of extracts from different parts ofVismia caulifloraagainst reactive oxygen and nitrogen species

“…The whole fruit extract exhibited the lower efficiency (3.6 ± 0.2 mg/mL) than other parts; nevertheless, its IC 50 value was similar to bixin (3 mg/mL), considered as a good scavenger of NO (Chisté et al, 2011). In relation to ONOO À , this RNS has been shown as a strong oxidizing and nitrating compound capable to oxidize a variety of biomolecules including lipids, proteins, carbohydrates, and DNA (Carr et al, 2000). Consequently, this RNS has been implicated in neurodegenerative disorders, Alzheimer's, Parkinson's, and cardiovascular diseases (Gomes et al, 2006).…”

“…However, the sustained NO generation can cause deleterious effect in tissues and it is involved in the pathogenesis of disease states like endotoxin shock and inflammation (Gomes et al, 2006 system during the oxidative burst, may react with each other, generating significant amounts of ONOO À , which is a strong oxidative molecule (Carr et al, 2000). In this study, all extracts of V. cauliflora were very efficient scavengers of NO, with low IC 50 values (varying from 0.9 to 2.2 mg/mL).…”

Antioxidants in Wild Mushrooms

“…• to produce significant amounts of peroxynitrite anion (ONOO ), which is a potent oxidising agent that can cause DNA fragmentation and lipid oxidation [28,29].…”