Apolipoprotein A-I Milano exhibits potent antioxidant activity on phospholipid surfaces
Apolipoprotein(apo)A-IMilano and apoA-IParis are rare cysteine variants of apoA-I that produce a HDL deficiency in the absence of cardiovascular disease in humans. This paradox provides the basis for the hypothesis that the cysteine variants posses a beneficial activity not associated with wild-type apoA-I (apoA-IWT). In this study, a unique antioxidant activity of apoA-IMilano and apoA-IParis is described. Antioxidant activity was observed using the monomeric form of the variants and was equally effective before and after initiation of oxidative events. ApoA-IMilano was twice as effective as apoA-IParis in preventing lipoxygenase-mediated oxidation of phospholipids; whereas, apoA-IWT was poorly active. ApoA-IMilano protected phospholipid from reactive oxygen species (ROS) generated via xanthine/xanthine oxidase (X/Xo) but failed to inhibit X/Xo induced reduction of cytochrome C. These results indicate that (1) the antioxidant activity of apoA-IMilano was dependent on phospholipid and (2) the cysteine variant was unable to directly quench ROS in the aqueous phase. There were no differences between lipid-free apoA-IMilano, apoA-IParis, and apoA-IWT in mediating the efflux of cholesterol from macrophages indicating the cysteine variants interacted normally with the ABCA1 efflux pathway. The results indicate that incorporation of a free thiol within an amphipathic alpha helix of apoA-I confers an antioxidant activity distinct from that of apoA-IWT. These studies are the first to relate addition-of-function to rare cysteine mutations in apoA-I primary sequence.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE; National Institutes of Health Grants HL59483 and HL55493, American Heart Association Western Affiliate Postdoctoral Fellowship 98-07 (US)
- DOE Contract Number:
- AC03-76SF00098
- OSTI ID:
- 840025
- Report Number(s):
- LBNL-48945; R&D Project: 860D13; TRN: US200509%%780
- Journal Information:
- Biochemistry, Vol. 41, Issue 6; Other Information: Journal Publication Date: 02/12/2002; PBD: 21 Sep 2001
- Country of Publication:
- United States
- Language:
- English
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