OXIDATIVE TYROSYLATION OF HIGH-DENSITY-LIPOPROTEIN BY PEROXIDASE ENHANCES CHOLESTEROL REMOVAL FROM CULTURED FIBROBLASTS AND MACROPHAGE FOAM CELLS
OXIDATIVE TYROSYLATION OF HIGH-DENSITY-LIPOPROTEIN BY PEROXIDASE ENHANCES CHOLESTEROL REMOVAL FROM CULTURED FIBROBLASTS AND MACROPHAGE FOAM CELLS
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DOI：
10.1073/pnas.90.14.6631
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发表时间：
1993-07-15
影响因子：
11.1
通讯作者：
HEINECKE, JW
中科院分区：
文献类型：
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作者：
FRANCIS, GA;MENDEZ, AJ;HEINECKE, JW
脂蛋白氧化被认为在动脉粥样硬化中起着关键作用，但其潜在的反应机制仍然知之甚少。我们探讨了高密度脂蛋白（HDL）被过氧化物酶生成的酪氨酸自由基氧化的可能性。HDL暴露于l -酪氨酸，H2O2和辣根过氧化物酶交联其载脂蛋白和显著增加的蛋白质相关荧光。该反应需要l -酪氨酸，但不需要游离金属离子；它被过氧化氢酶或血红素毒素氨三唑阻断。在过氧化物酶/ l -酪氨酸/H2O2修饰的HDL载脂蛋白中检测到二酪氨酸和其他酪氨酸氧化产物，提示酪氨酸自由基参与了该反应途径。进一步的证据表明酪氨酸化HDL比HDL更有效地去除培养细胞中的胆固醇。酪氨酸化HDL比HDL更有效地抑制通过酰基辅酶a：胆固醇酰基转移酶反应的胆固醇酯化，刺激[C-14]醋酸盐并入[C-14]胆固醇，并消耗人皮肤成纤维细胞中的胆固醇酯储存。此外，小鼠巨噬细胞泡沫细胞暴露于酪氨酸化HDL显著降低胆固醇酯和游离胆固醇质量。我们最近发现髓过氧化物酶，一种由活化的吞噬细胞分泌的血红素蛋白，也能将l -酪氨酸转化为o，o'-二酪氨酸。这提高了髓过氧化物酶产生的酪氨酸自由基可能改变HDL的可能性，使脂蛋白保护动脉壁免受病理性胆固醇积累。
Lipoprotein oxidation is thought to play a pivotal role in atherogenesis, yet the underlying reaction mechanisms remain poorly understood. We have explored the possibility that high density lipoprotein (HDL) might be oxidized by peroxidase-generated tyrosyl radical. Exposure of HDL to L-tyrosine, H2O2, and horseradish peroxidase crosslinked its apolipoproteins and strikingly increased protein-associated fluorescence. The reaction required L-tyrosine but was independent of free metal ions; it was blocked by either catalase or the heme poison aminotriazole. Dityrosine and other tyrosine oxidation products were detected in the apolipoproteins of HDL modified by the peroxidase/L-tyrosine/H2O2, system, implicating tyrosyl radical in the reaction pathway. Further evidence suggests that tyrosylated HDL removes cholesterol from cultured cells more effectively than does HDL. Tyrosylated HDL was more potent than HDL at inhibiting cholesterol esterification by the acyl-CoA:cholesterol acyltransferase reaction, stimulating the incorporation of [C-14]acetate into [C-14]cholesterol, and depleting cholesteryl ester stores in human skin fibroblasts. Moreover, exposure of mouse macrophage foam cells to tyrosylated HDL markedly diminished cholesteryl ester and free cholesterol mass. We have recently found that myeloperoxidase, a heme protein secreted by activated phagocytes, can also convert L-tyrosine to o,o'-dityrosine. This raises the possibility that myeloperoxidase-generated tyrosyl radical may modify HDL, enabling the lipoprotein to protect the artery wall against pathological cholesterol accumulation.