Human carotid lesion linoleic acid hydroperoxide inhibits paraoxonase 1 (PON1) activity via reaction with PON1 free sulfhydryl cysteine 284

被引:36
作者
Tavori, Hagai [1 ,2 ,3 ]
Aviram, Michael [3 ]
Khatib, Soliman [1 ,2 ]
Musa, Ramadan [1 ,2 ]
Mannheim, Dalit [4 ]
Karmeli, Ron [4 ]
Vaya, Jacob [1 ,2 ]
机构
[1] MIGAL Galilee Technol Ctr, Oxidat Stress Res Lab, IL-11016 Kiryat Shmona, Israel
[2] Tel Hai Coll, Upper Galilee, Israel
[3] Technion Israel Inst Technol, Rambam Med Ctr, Lipid Res Lab, Rappaport Family Inst Res Med Sci, IL-31096 Haifa, Israel
[4] Carmel Hosp, Dept Vasc Surg, Haifa, Israel
基金
以色列科学基金会;
关键词
Atherosclerosis; Carotid lesion; Free thiols; Linoleic acid hydroperoxide; Oxidative stress; Paraoxonase; 1; Free radicals; LOW-DENSITY-LIPOPROTEIN; HUMAN ATHEROSCLEROTIC LESIONS; LACTONASE ACTIVITY; CIGARETTE-SMOKE; LIPID PEROXIDES; SERUM; HDL; DECREASE; CELLS; OXIDATION;
D O I
10.1016/j.freeradbiomed.2010.10.708
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Paraoxonase 1 (PON1) is an HDL-associated lactonase with antiatherogenic properties. These include dampening the oxidation properties of human carotid lesion lipid extract (LLE), which in turn inactivates the enzyme. The aims of this study were to identify the PON1 inhibitor in LLE and explore the mechanism of inhibition. LLE inhibited both recombinant PON1 and HDL-PON1 lactonase activity in a dose- and time-dependent manner. Addition of antioxidants or electrophiles to LLE did not prevent PON1 inhibition. LLE was unable to inhibit a PON1 mutant lacking Cys284, whereas it did inhibit all other PON1 mutants tested. The inhibitor in the LLE was identified as linoleic acid hydroperoxide (LA-OOH) and inhibition was specific to this hydroperoxide. During its inhibition, PON1 acted like a peroxidase enzyme, reducing LA-OOH to LA-hydroxide via its Cys284. A similar reaction occurred with external thiols, such as DDT or cysteine, which also prevented PON1 inhibition and restored enzyme activity after inhibition. Thus, the antiatherogenic properties of HDL could be, at least in part, related to the sulfhydryl-reducing characteristics of its associated PON1, which are further protected and recycled by the sulfhydryl amino acid cysteine. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:148 / 156
页数:9
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