Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apolipoprotein A-I(Milano) (apoA-I(Milano)) and apoA-I(Paris) 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 possess a beneficial activity not associated with wild-type apoA-I (apoA-I(WT)). In this study, a unique antioxidant activity of apoA-I(Milano) and apoA-I(Paris) is described. ApoA-I(Milano) was twice as effective as apoA-I(Paris) in preventing lipoxygenase-mediated oxidation of phospholipids, whereas apoA-I(WT) was poorly active. Antioxidant activity was observed using the monomeric form of the variants and was equally effective before and after initiation of oxidative events. ApoA-I(Milano) 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 apoA-I(Milano) was unable to directly quench ROS in the aqueous phase. There were no differences between lipid-free apoA-I(Milano,) apoA-I(Paris), and apoA-I(WT) in mediating the efflux of cholesterol from macrophages, indicating that 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-I(WT). These studies are the first to relate gain of function to rare cysteine mutations in the apoA-I primary sequence.
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PMID:Apolipoprotein A-I(Milano) and apolipoprotein A-I(Paris) exhibit an antioxidant activity distinct from that of wild-type apolipoprotein A-I. 1182 56

The relationship between high-density lipoprotein and pulmonary function is unclear. To determine mechanistic relationships we investigated the effects of genetic deletion of apolipoprotein A-I (apoA-I) on plasma lipids, paraoxonase (PON1), pro-inflammatory HDL (p-HDL), vasodilatation, airway hyperresponsiveness and pulmonary oxidative stress, and inflammation. ApoA-I null (apoA-I(-/-)) mice had reduced total and HDL cholesterol but increased pro-inflammatory HDL compared with C57BL/6J mice. Although PON1 protein was increased in apoA-I(-/-) mice, PON1 activity was decreased. ApoA-I deficiency did not alter vasodilatation of facialis arteries, but it did alter relaxation responses of pulmonary arteries. Central airway resistance was unaltered. However, airway resistance mediated by tissue dampening and elastance were increased in apoA-I(-/-) mice, a finding also confirmed by positive end-expiratory pressure (PEEP) studies. Inflammatory cells, collagen deposition, 3-nitrotyrosine, and 4-hydroxy-2-nonenal were increased in apoA-I(-/-) lungs but not oxidized phospholipids. Colocalization of 4-hydroxy-2-nonenal with transforming growth factor beta-1 (TGFbeta-1 was increased in apoA-I(-/-) lungs. Xanthine oxidase, myeloperoxidase and endothelial nitric oxide synthase were increased in apoA-I(-/-) lungs. Dichlorodihydrofluorescein-detectable oxidants were increased in bronchoalveolar lavage fluid (BALF) in apoA-I(-/-) mice. In contrast, BALF nitrite+nitrate levels were decreased in apoA-I(-/-) mice. These data demonstrate that apoA-I plays important roles in limiting pulmonary inflammation and oxidative stress, which if not prevented, will decrease pulmonary artery vasodilatation and increase airway hyperresponsiveness.
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PMID:Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung. 2049 9