Site-specific Nitration of Apolipoprotein A-I at Tyrosine 166 Is Both Abundant within Human Atherosclerotic Plaque and Dysfunctional

Abstract

Background:The functional importance of apolipoprotein A-I (apoA-I) nitration at tyrosine 166 (Tyr 166 ) in vivo is controversial. Results: Nitrotyrosine 166-apoA-I accounts for 8% of apoA-I within human atheroma, is not HDL-associated, and is functionally impaired. Conclusion: Buoyant density ultracentrifugation of HDL can lead to erroneous results, particularly with modified apoA-I forms. Significance: Detection and quantification of nitrotyrosine 166-apoA-I may provide insights into a pathophysiological process within the artery wall.

Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I

“…Although the level of apoA-I Met oxidation in human atherosclerotic lesions is unknown, compelling evidence suggests that in atherosclerotic plaques, apoA-I Met oxidation could reach levels similar to those produced by MPO oxidation in this study. Recently, the levels of apoA-I harboring a 3-nitrotyrosine (NO 2 -Tyr) in position 166 or a 2-hydroxy-L-tryptophan (2-OH-Trp) in position 72 were quantified in human plasma and in atherosclerotic plaques (10,11). The levels of NO 2 -Tyr-apoA-I and 2-OH-TrpapoA-I in atherosclerotic lesions were respectively ϳ50-and ⁄2 were calculated from the data fitting and defined as the time at which the ThT fluorescence reached 50% of the maximal value measured for H 2 O 2 -WT-rapoA-I.…”

“…The identification of apoA-I as the main component of atherosclerosis-associated amyloids suggests a link between local apoA-I oxidation and increased amyloidogenic potential of oxidized wild-type apoA-I. MPO could be the primary mediator of this oxidation (6,8,11,12). Unfortunately, the oxidation state of apoA-I in amyloid clinical samples composed of wild-type apoA-I (full-length or fragments) is largely unknown (23), and this causal link remains hypothetical.…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…Oxidative modification of Met-148 or nitration of Tyr-166 by MPO in apoA-I was also associated with a loss of apoA-I-mediated activation of lecithin:cholesterol acyltransferase (LCAT), 130,133,136 which is crucial to help maintain a concentration gradient for cholesterol efflux from the cell to the HDL particle surface. The injection of purified MPO into mice reduced the net movement of labeled-cholesterol from macrophages to plasma and feces.…”

“…41 Likewise, differences in cholesterol efflux capacity have been attributed to differences in HDL particle number, HDL subclass distribution, phospholipid composition, 86 the presence of SAA, 58-61 or posttranslational modifications. [127][128][129][130][131][132] As yet it is not clear whether these findings reflect redundancy or complexity of HDL interactions with endothelial cells or result from confounding.…”

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…In serum, this variant is existed in lipid-poor state due to a low lipid-binding capacity and 10-fold reduced ability to bind LCAT. 75 ApoA1 oxidation and chlotorination is mainly mediated by neutrophil myeloperoxidase (MPO). 76 MPO-mediated oxidation of Trp 72 leads to the formation of the oxTrp72-ApoA1 variant that is abundantly present (20% of total apoA1 in atherosclerotic vessels) in the plaque and lack an ability to activate ABCA1.…”