Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl)

Abstract

Oxidative modification of HDLs (high-density lipoproteins) by MPO (myeloperoxidase) compromises its anti-atherogenic properties, which may contribute to the development of atherosclerosis. Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined. In the present study, we characterize the structural and functional modifications of lipid-free apoA-I and rHDL (reconstituted discoidal HDL) containing apoA-I complexed with phospholipid, induced by HOSCN and its decomposition product, OCN- (cyanate). Treatment of apoA-I with HOSCN resulted in the oxidation of tryptophan residues, whereas OCN- induced carbamylation of lysine residues to yield homocitrulline. Tryptophan residues were more readily oxidized on apoA-I contained in rHDLs. Exposure of lipid-free apoA-I to HOSCN and OCN- significantly reduced the extent of cholesterol efflux from cholesterol-loaded macrophages when compared with unmodified apoA-I. In contrast, HOSCN did not affect the anti-inflammatory properties of rHDL. The ability of HOSCN to impair apoA-I-mediated cholesterol efflux may contribute to the development of atherosclerosis, particularly in smokers who have high plasma levels of SCN- (thiocyanate).

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…ApoA1 exposed to cyanate (HOCN), a product of HOSCN decomposition, lack the ability to control RCT and become pro-inflammatory. 80,81 Compared with native HDL, in ApoE-deficient mice, MPOmodified HDL lose anti-atherogenic properties as they unable to stabilize plaque, prevent foam cell formation, and suppress formation of macrophages with the pro-inflammatory phenotype. 34 MPO-modified HDL cannot bind to the HDL receptor and scavenger receptor B1, and promote proinflammatory activities such as upregulation of nuclear factor (NF)-κB and expression of adhesion molecules by ECs.…”

Comparative reactivity of the myeloperoxidase-derived oxidants HOCl and HOSCN with low-density lipoprotein (LDL): Implications for foam cell formation in atherosclerosis

“…34 Low-density lipoprotein (LDL) is the source of this lipid, owing to the uptake of oxidised LDL by scavenger 35 receptors. Myeloperoxidase (MPO) released by leukocytes during inflammation produces oxidants that 36 are implicated in atherosclerosis.…”

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

“…We demonstrated previously that apoA-I recovered from human atherosclerotic lesions is heavily oxidized (7)(8)(9)18), a finding that others have replicated (6,19,20). Proteomic identification of oxidatively modified sites within apoA-I isolated from atherosclerotic lesion by immunoprecipitation with apoA-I-specific antibodies identified a number of preferred residues for MPO-and NO-derived oxidant PTMs (8,9).…”