Ismael Fahd O, Proudfoot Julie M, Brown Bronwyn E, van Reyk David M, Croft Kevin D, Davies Michael J, Hawkins Clare L
The Heart Research Institute, 7 Eliza St, Newtown, NSW 2042, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
School of Medicine and Pharmacology, University of Western Australia, Level 4 Medical Research Foundation Building, 50 Murray St, Perth, WA 6000, Australia.
Arch Biochem Biophys. 2015 May 1;573:40-51. doi: 10.1016/j.abb.2015.03.008. Epub 2015 Mar 18.
Atherosclerosis is characterised by the accumulation of lipids within macrophages in the artery wall. Low-density lipoprotein (LDL) is the source of this lipid, owing to the uptake of oxidised LDL by scavenger receptors. Myeloperoxidase (MPO) released by leukocytes during inflammation produces oxidants that are implicated in atherosclerosis. Modification of LDL by the MPO oxidant hypochlorous acid (HOCl), results in extensive lipid accumulation by macrophages. However, the reactivity of the other major MPO oxidant, hypothiocyanous acid (HOSCN) with LDL is poorly characterised, which is significant given that thiocyanate is the favoured substrate for MPO. In this study, we comprehensively compare the reactivity of HOCl and HOSCN with LDL, and show key differences in the profile of oxidative damage observed. HOSCN selectively modifies Cys residues on apolipoprotein B100, and oxidises cholesteryl esters resulting in formation of lipid hydroperoxides, 9-hydroxy-10,12-octadecadienoic acid (9-HODE) and F2-isoprostanes. The modification of LDL by HOSCN results macrophage lipid accumulation, though generally to a lesser extent than HOCl-modified LDL. This suggests that a change in the ratio of HOSCN:HOCl formation by MPO from variations in plasma thiocyanate levels, will influence the nature of LDL oxidation in vivo, and has implications for the progression of atherosclerosis.
动脉粥样硬化的特征是动脉壁内巨噬细胞中脂质的积累。低密度脂蛋白（LDL）是这种脂质的来源，这是由于清道夫受体摄取了氧化型LDL。白细胞在炎症过程中释放的髓过氧化物酶（MPO）产生与动脉粥样硬化有关的氧化剂。MPO氧化剂次氯酸（HOCl）对LDL的修饰导致巨噬细胞大量脂质积累。然而，另一种主要的MPO氧化剂次硫氰酸（HOSCN）与LDL的反应性却鲜为人知，鉴于硫氰酸盐是MPO的首选底物，这一点很重要。在本研究中，我们全面比较了HOCl和HOSCN与LDL的反应性，并展示了观察到的氧化损伤特征的关键差异。HOSCN选择性修饰载脂蛋白B100上的半胱氨酸残基，并氧化胆固醇酯，导致脂质氢过氧化物、9-羟基-10,12-十八碳二烯酸（9-HODE）和F2-异前列腺素的形成。HOSCN对LDL的修饰导致巨噬细胞脂质积累，尽管一般程度低于HOCl修饰的LDL。这表明，由于血浆硫氰酸盐水平的变化，MPO形成的HOSCN:HOCl比例的改变将影响体内LDL氧化的性质，并对动脉粥样硬化的进展产生影响。
