Myeloperoxidase Targets Apolipoprotein A-I, the Major High Density Lipoprotein Protein, for Site-Specific Oxidation in Human Atherosclerotic Lesions

Abstract

Background:Oxidation of apolipoprotein A-I by myeloperoxidase has been proposed to deprive HDL of its cardioprotective effects. Results: Tyrosine 192 is the major site of chlorination in apoA-I in both plasma and lesion HDL isolated from humans. Conclusion: Chlorination of apolipoprotein A-I by myeloperoxidase may contribute to generation of a dysfunctional form of HDL in vivo. Significance: Quantifying apolipoprotein A-I chlorination might help diagnose and perhaps treat human cardiovascular disease.

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

“…Following immunoprecipitation of total apoA-I from homogenates prepared from the atherosclerotic artery wall, it was reported that NO 2 -Tyr 166 modification of apoA-I was an abundant PTM in vivo through proteomics studies (8). In contrast, in studies that followed using buoyant density centrifugation to isolate HDL-like particles, it was concluded that nitration of tyrosine at this site on apoA-I is an exceedingly low abundance product and therefore presumably of little physiologically relevance (22). The present studies unambiguously showed that nitration of apoA-I at tyrosine 166 is an exceptionally abundant modification in apoA-I in the diseased artery wall where ϳ1 of every 12 apoA-I molecules recovered harbors this PTM.…”

“…Proteomics analysis of buoyant densityisolated HDL-like fractions confirms tyrosine 192 as a preferred oxidation site on apoA-I through MPO-catalyzed chlorination in both human plasma-and lesion-derived apoA-I (21,22). The major site of nitration in plasma-derived apoA-I in HDL was also reported to be tyrosine 192, whereas tyrosine 18 was found to be a major site reported from lesion "HDL-like" particlelocalized apoA-I (22).…”

“…Proteomics analysis of buoyant densityisolated HDL-like fractions confirms tyrosine 192 as a preferred oxidation site on apoA-I through MPO-catalyzed chlorination in both human plasma-and lesion-derived apoA-I (21,22). The major site of nitration in plasma-derived apoA-I in HDL was also reported to be tyrosine 192, whereas tyrosine 18 was found to be a major site reported from lesion "HDL-like" particlelocalized apoA-I (22). In these latter studies where apoA-I was recovered from plasma or lesions by floating HDL, little nitration at tyrosine 166 was observed, and the involvement of this site in modification was suggested to have little biological relevance (22).…”

“…The major site of nitration in plasma-derived apoA-I in HDL was also reported to be tyrosine 192, whereas tyrosine 18 was found to be a major site reported from lesion "HDL-like" particlelocalized apoA-I (22). In these latter studies where apoA-I was recovered from plasma or lesions by floating HDL, little nitration at tyrosine 166 was observed, and the involvement of this site in modification was suggested to have little biological relevance (22). Thus, there exists a discrepancy of the importance of modification within apoA-I with regard to the abundance and functional significance of tyrosine 166 oxidative modification.…”

“…Other investigators have studied oxidative PTMs on apoA-I present in atherosclerotic lesions not by immunoprecipitating total apoA-I but rather exclusively by "floating" HDL-like particles (d ϭ 1.063-1.21 g/ml) using buoyant density ultracentrifugation (6,7,19,21,22). Proteomics analysis of buoyant densityisolated HDL-like fractions confirms tyrosine 192 as a preferred oxidation site on apoA-I through MPO-catalyzed chlorination in both human plasma-and lesion-derived apoA-I (21,22).…”