Chloroquine stimulates nitric oxide synthesis in murine, porcine, and human endothelial cells
Chloroquine stimulates nitric oxide synthesis in murine, porcine, and human endothelial cells
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DOI：
10.1172/jci1052
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发表时间：
1998-08-01
影响因子：
15.9
通讯作者：
Bosia, A
中科院分区：
文献类型：
--
作者：
Ghigo, D;Aldieri, E;Bosia, A
一氧化氮（NO）是一种自由基，参与许多细胞功能的调节和几种疾病的表达。我们已经发现，抗疟药，氯喹，是能够刺激一氧化氮合酶（NOS）的活性在小鼠，猪，和人的内皮细胞在体外：酶活性的增加是依赖于从头合成的一些调节蛋白，因为它是由放线菌酮抑制，但不伴随着诱导型或组成型NOS亚型的表达增加。NO合成增加，至少部分，负责氯喹诱导的细胞增殖抑制：事实上，NOS抑制剂逆转药物诱发的小鼠和猪内皮细胞的有丝分裂和鸟氨酸脱羧酶活性的阻断。氯喹的NOS激活作用依赖于其弱碱性，因为它也由另一种溶酶体促动剂氯化铵发挥作用。这两种化合物激活NOS通过限制铁的可用性：它们对NO合成的刺激作用和对细胞增殖的抑制作用被还原铁补充氮三乙酸铁，并模仿孵育与去铁胺，我们的研究结果表明，NO合成可以刺激内皮细胞氯喹通过损害铁代谢。
Nitric oxide (NO) is a free radical involved in the regulation of many cell functions and in the expression of several diseases. We have found that the antimalarial and antiinflammatory drug, chloroquine, is able to stimulate NO synthase (NOS) activity in murine, porcine, and human endothelial cells in vitro: the increase of enzyme activity is dependent on a de novo synthesis of some regulatory protein, as it is inhibited by cycloheximide but is not accompanied by an increased expression of inducible or constitutive NOS isoforms. Increased NO synthesis is, at least partly, responsible for chloroquine-induced inhibition of cell proliferation: indeed, NOS inhibitors revert the drug-evoked blockage of mitogenesis and ornithine decarboxylase activity in murine and porcine endothelial cells. The NOS-activating effect of chloroquine is dependent on its weak base properties, as it is exerted also by ammonium chloride, another lysosomotropic agent. Both compounds activate NOS by limiting the availability of iron: their stimulating effects on NO synthesis and inhibiting action on cell proliferation are reverted by iron supplementation with ferric nitrilotriacetate, and are mimicked by incubation with desferrioxamine, Our results suggest that NO synthesis can be stimulated in endothelial cells by chloroquine via an impairment of iron metabolism.