Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease

Abstract

In recent studies we demonstrated that systemic levels of protein-bound nitrotyrosine (NO(2)Tyr) and myeloperoxidase (MPO), a protein that catalyzes generation of nitrating oxidants, serve as independent predictors of atherosclerotic risk, burden, and incident cardiac events. We now show both that apolipoprotein A-I (apoA-I), the primary protein constituent of HDL, is a selective target for MPO-catalyzed nitration and chlorination in vivo and that MPO-catalyzed oxidation of HDL and apoA-I results in selective inhibition in ABCA1-dependent cholesterol efflux from macrophages. Dramatic selective enrichment in NO(2)Tyr and chlorotyrosine (ClTyr) content within apoA-I recovered from serum and human atherosclerotic lesions is noted, and analysis of serum from sequential subjects demonstrates that the NO(2)Tyr and ClTyr contents of apoA-I are markedly higher in individuals with cardiovascular disease (CVD). Analysis of circulating HDL further reveals that higher NO(2)Tyr and ClTyr contents of the lipoprotein are each significantly associated with diminished ABCA1-dependent cholesterol efflux capacity of the lipoprotein. MPO as a likely mechanism for oxidative modification of apoA-I in vivo is apparently facilitated by MPO binding to apoA-I, as revealed by cross-immunoprecipitation studies in plasma, recovery of MPO within HDL-like particles isolated from human atheroma, and identification of a probable contact site between the apoA-I moiety of HDL and MPO. To our knowledge, the present results provide the first direct evidence for apoA-I as a selective target for MPO-catalyzed oxidative modification in human atheroma. They also suggest a potential mechanism for MPO-dependent generation of a proatherogenic dysfunctional form of HDL in vivo.

Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL

“…We and others have previously shown that HDL isolated from atherosclerotic lesions contains higher levels of oxidized amino acids than HDL isolated from plasma (10)(11)(12). This observation raises the possibility that proteins found in HDL from CAD patients might come in part from the artery wall.…”

“…Moreover, both oxidative modifications and alterations in the protein cargo of HDL may alter its biological activity, creating potentially proatherogenic particles (8,9). We and others recently showed that HDL isolated from plasma of patients with known coronary artery disease (CAD) is oxidatively modified and that oxidation impairs reverse cholesterol transport mediated by HDL (10)(11)(12).…”

Myeloperoxidase binds to non-vital spermatozoa on phosphatidylserine epitopes

“…The strong cationic enzyme MPO interacts easily with acidic proteins such as albumin, a 1 -antiproteinase, fibronectin, apolipoprotein A-1 and ceruloplasmin [25,[29][30][31][32][33][34]. Attachment of MPO to negatively charged membrane sites have also been reported whereby a heparin-heparan-binding site was assumed [30,35].…”

Experimental Models for the Investigation of High-Density Lipoprotein–Mediated Cholesterol Efflux

“…Serum amyloid A (SAA) replaces apoA-I in HDL particles, generating lipid-free apoA-I, which is more rapidly cleared by the kidney [21•]. Leukocyte myeloperoxidase-induced oxidation also generates "dysfunctional" HDL-C with pro-inflammatory properties and with a reduced ability of apoA-I to promote cholesterol efflux via ABCA1 [22]. Finally, non-enzymatic glycation of apoA-I has been shown to impair its ability to promote ABCA1 stabilization and ABCA1-dependent cholesterol efflux, and activation of LCAT and its anti-inflammatory properties [23].…”