Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL
Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL
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DOI：
10.1172/jci119634
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发表时间：
1997-09-01
影响因子：
15.9
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
--
作者：
Ishikawa, K;Navab, M;Lusis, AJ
血红素的分解代谢过程产生抗氧化剂胆绿素和胆红素，以及强有力的促氧化剂游离铁。由于这些产物对氧化应激具有相反的作用，目前尚不清楚血红素分解代谢是促进还是抑制炎症过程，包括动脉粥样硬化病变的形成。血红素加氧酶(HO)催化血红素分解代谢的限速步骤。我们使用人主动脉内皮细胞和血管平滑肌细胞共培养来研究HO在早期动脉粥样硬化中的可能作用。血红素加氧酶-L(HO-1)是HO的诱导型亚型，轻度氧化的低密度脂蛋白可诱导HO的高度诱导，氯化高铁血红素可增强HO的诱导作用。这种增强的HO-1诱导导致单核细胞对低密度脂蛋白氧化反应的趋化性降低。相反，一种特定的抑制剂，锡原卟啉IX抑制HO，增强了趋化作用。此外，用HO的产物胆绿素或胆红素预处理会降低趋化性。轻度氧化的低密度脂蛋白中的氧化磷脂似乎是HO-I诱导的原因，因为氧化的而不是天然的含花生四烯酸的磷脂也能诱导HO-1。这些结果表明，轻度氧化的低密度脂蛋白诱导的HO-I可能通过产生抗氧化剂胆绿素和胆红素来保护动脉壁细胞的炎症反应。
Heme catabolic processes produce the antioxidants biliverdin and bilirubin, as well as the potent prooxidant free iron. Since these products have opposing effects on oxidative stress, it is not clear whether heme catabolism promotes or inhibits inflammatory processes, including atherosclerotic lesion formation. Heme oxygenase (HO) catalyzes the rate-limiting step of heme catabolism. We used cocultures of human aortic endothelial cells and smooth muscle cells to examine the possible role of HO in early atherosclerosis. Heme oxygenase-l (HO-1), the inducible isoform of HO, was highly induced by mildly oxidized LDL, and augmented induction was observed with hemin pretreatment. This augmented HO-1 induction resulted in the reduction of monocyte chemotaxis in response to LDL oxidation. Conversely, inhibition of HO by a specific inhibitor, Sn-protoporphyrin IX, enhanced chemotaxis. Furthermore, pretreatment with biliverdin or bilirubin, the products of HO, reduced chemotaxis. Oxidized phospholipids in the mildly oxidized LDL appear to be responsible for HO-I induction, since oxidized but not native arachidonic acid-containing phospholipids also induced HO-1. These results suggest that HO-I induced by mildly oxidized LDL may protect against the induction of inflammatory responses in artery wall cells through the production of the antioxidants biliverdin and bilirubin.