Carbonyl scavenger and antiatherogenic effects of hydrazine derivatives
Carbonyl scavenger and antiatherogenic effects of hydrazine derivatives
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DOI：
10.1016/j.freeradbiomed.2008.08.026
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发表时间：
2008-11-15
影响因子：
7.4
通讯作者：
Negre-Salvayre, Anne
中科院分区：
文献类型：
--
作者：
Galvani, Sylvain;Coatrieux, Christelle;Negre-Salvayre, Anne
多不饱和脂肪酸氧化产生的反应性羰基化合物（RCC）通过在游离氨基和巯基残基上形成加合物（羰基应激）来逐渐改变细胞和组织蛋白质。羰基清除剂可以中和RCC，但其在动脉粥样硬化中的保护作用尚未得到广泛研究。我们报告的羰基清除剂和抗动脉粥样硬化性质的肼衍生物，即肼屈嗪，抗高血压药物，异烟肼，抗结核药，和两种抗抑郁药，苯乙肼和异丙烟肼。这些药物在阻止由平滑肌细胞（SMC）介导的LDL氧化方面效果不佳，但抑制UV氧化LDL（oxLDL）和4-羟基壬烯醛（4-HNE）的毒性。肼衍生物通过抑制游离氨基含量的减少、羰基化蛋白的增加和PDGFR上4-HNE加合物的形成，阻止了人巨噬细胞U937细胞中LDL氧化导致的泡沫细胞的形成，并阻断了SMC中的羰基应激。对apoE-/-小鼠补充药物（饮用水中30 mg/L）进行的实验研究显示，显著的羰基应激抑制与动脉粥样硬化病变发展的净减少相关。总之，这些数据表明，肼衍生物具有羰基清除剂和抗动脉粥样硬化的性质，这为动脉粥样硬化及其心血管并发症开辟了新的治疗方法。(C)2008年爱思唯尔公司All rights reserved.
Reactive carbonyl compounds (RCC) generated by polyunsaturated fatty acid oxidation alter progressively cellular and tissular proteins by forming adducts on free amino groups and thiol residues (carbonyl stress). Carbonyl scavengers may neutralize RCC, but their protective effect in atherosclerosis has not been extensively studied. We report the carbonyl scavenger and antiatherogenic properties of hydrazine derivatives, namely hydralazine, an antihypertensive drug, isoniazid, an antituberculosis agent, and two antidepressants, phenelzine and iproniazid. These drugs were Poorly efficient in preventing the oxidation of LDL mediated by smooth muscle cells (SMCs), but inhibited the toxicity of UV-oxidized LDL (oxLDL) and of 4-hydroxynonenal (4-HNE). Hydrazine derivatives prevented the formation of foam cells resulting from LDL oxidation in human macrophagic U937 cells, and blocked the carbonyl stress in SMCs, by inhibiting the decrease in free amino group content, the increase in carbonylated proteins, and the formation of 4-HNE adducts on PDGFR. Experimental studies carried out on apoE-/- mice supplemented with drugs (30 mg/L in drinking water) showed a significant carbonyl stress inhibition correlated with a net reduction of atherosclerotic lesion development. In conclusion, these data indicate that hydrazine derivatives exhibit carbonyl scavenger and antiatherogenic properties, which opens novel therapeutical approaches for atherosclerosis and its cardiovascular complications. (C) 2008 Elsevier Inc. All rights reserved.