Detection of HOCl-mediated protein oxidation products in the extracellular matrix of human atherosclerotic plaques

Abstract

Oxidation is believed to play a role in atherosclerosis. Oxidized lipids, sterols and proteins have been detected in early, intermediate and advanced human lesions at elevated levels. The spectrum of oxidized side-chain products detected on proteins from homogenates of advanced human lesions has been interpreted in terms of the occurrence of two oxidative mechanisms, one involving oxygen-derived radicals catalysed by trace transition metal ions, and a second involving chlorinating species (HOCl or Cl2), generated by the haem enzyme myeloperoxidase (MPO). As MPO is released extracellularly by activated monocytes (and possibly macrophages) and is a highly basic protein, it would be expected to associate with polyanions such as the glycosaminoglycans of the extracellular matrix, and might result in damage being localized at such sites. In this study proteins extracted from extracellular matrix material obtained from advanced human atherosclerotic lesions are shown to contain elevated levels of oxidized amino acids [3,4-dihydroxyphenylalanine (DOPA), di-tyrosine, 2-hydroxyphenylalanine (o-Tyr)] when compared with healthy (human and pig) arterial tissue. These matrix-derived materials account for 83—96% of the total oxidized protein side-chain products detected in these plaques. Oxidation of matrix components extracted from healthy artery tissue, and model proteins, with reagent HOCl is shown to give rise to a similar pattern of products to those detected in advanced human lesions. The detection of elevated levels of DOPA and o-Tyr, which have been previously attributed to the occurrence of oxygen-radical-mediated reactions, by HOCl treatment, suggests an alternative route to the formation of these materials in plaques. This is believed to involve the formation and subsequent decomposition of protein chloramines.

Advanced oxidation protein products and malondialdehyde — the new biological markers of oxidative stress — are elevated in postmenopausal women

“…These products originate as the result of free radical action on proteins and may act as inflammatory mediators triggering the oxidative 'ignition' of neutrophils, monocytes and T-lymphocytes, thus leading to up regulation and excessive stimulation of dendritic cells. These processes may account for immune disorders in atherosclerosis [39]. On the other hand, the antagonistic effect of AOPPs on high-density lipoprotein receptor by blocking HDL receptor scavenger receptor class B type I (SR-BI) gives rise to inhibition of HDL, association to SR-BI and SR-BI-mediated cholesteryl ester uptake [40].…”

Role of Oxidative Modifications in Atherosclerosis

“…The production of HOCl is also associated with metalloproteinase activity, both directly and indirectly. With regard to the former, HOCl can fragment components of the extracellular matrix (1063), and there is evidence for this occurring in atherosclerotic plaques (1064). Matrix metalloproteinases are converted from a proenzyme to the activated form through amino-terminal cleavage (1029), a process that is facilitated by HOCl (278,1025).…”

Oxidative lipid, protein, and DNA damage as oxidative stress markers in vascular complications of diabetes mellitus

“…Recently, a new marker of protein oxidation, advanced oxidation protein products (AOPP), has begun to attract the attention of various investigators [5][6][7][8]. AOPP are proteins, predominantly albumin and its aggregates, which have been damaged by oxidative stress [9].…”