Antiatherogenic Effect of Bisvanillyl-Hydralazone, a New Hydralazine Derivative with Antioxidant, Carbonyl Scavenger, and Antiapoptotic Properties
Antiatherogenic Effect of Bisvanillyl-Hydralazone, a New Hydralazine Derivative with Antioxidant, Carbonyl Scavenger, and Antiapoptotic Properties
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DOI：
10.1089/ars.2010.3321
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发表时间：
2011-06-01
影响因子：
6.6
通讯作者：
Negre-Salvayre, Anne
中科院分区：
文献类型：
--
作者：
Bouguerne, Benaissa;Belkheiri, Nadji;Negre-Salvayre, Anne
血管壁内产生的活性氧（ROS）触发低密度脂蛋白（LDL）氧化、脂质过氧化和羰基应激，参与动脉粥样硬化形成。我们最近报道了抗高血压药物肼苯哒嗪具有羰基清除剂和抗动脉粥样硬化的特性，但只有中等的抗氧化活性，因此需要高浓度才能抑制LDL氧化。我们的目标是开发具有抗氧化剂和羰基清除剂特性的试剂。我们合成了一个新的肼苯哒嗪衍生物，双香草基肼苯哒嗪（BVH）。BVH强烈抑制铜和人内皮细胞（HMEC-1）诱导的LDL氧化，并阻止巨噬泡沫细胞的形成。BVH减少氧化LDL（oxLDL）诱导的细胞外ROS（超氧阴离子和过氧化氢）生成，以及细胞内氧化应激和蛋白酶体激活、NF κ B激活和oxLDL介导的促炎信号传导。与此同时，BVH防止羰基应激诱导的氧化低密度脂蛋白对细胞蛋白质，并阻断凋亡级联反应的抑制Bid裂解，细胞色素C释放，和DEVDase激活。最后，BVH在apoE（-/-）小鼠中预防动脉粥样硬化和羰基应激。总之，BVH是一类新的抗氧化剂和羰基清除剂的原型，设计用于动脉粥样硬化的新治疗方法。抗氧化剂。氧化还原信号。14，2093-2106。
Reactive oxygen species (ROS) generated within the vascular wall trigger low-density lipoprotein (LDL) oxidation, lipid peroxidation, and carbonyl stress that are involved in atherogenesis. We recently reported that the antihypertensive drug, hydralazine, exhibits carbonyl scavenger and antiatherogenic properties, but only moderate antioxidant activity, so that high concentrations are required for inhibiting LDL oxidation. We aimed to develop agents sharing both antioxidant and carbonyl scavenger properties. We have synthesized a new hydralazine derivative, the bisvanillyl-hydralazone (BVH). BVH strongly inhibited LDL oxidation induced by copper and by human endothelial cells (HMEC-1), and prevented the formation of macrophagic foam cells. BVH reduced both the extracellular generation of ROS (superoxide anion and hydrogen peroxide) induced by oxidized LDL (oxLDL), as well as intracellular oxidative stress and proteasome activation, NFkappaB activation, and oxLDL-mediated proinflammatory signaling. In parallel, BVH prevented the carbonyl stress induced by oxLDL on cellular proteins, and blocked the apoptotic cascade as assessed by the inhibition of Bid cleavage, cytochrome C release, and DEVDase activation. Lastly, BVH prevented atherogenesis and carbonyl stress in apoE(-/-) mice. In conclusion, BVH is the prototype of a new class of antioxidant and carbonyl scavenger agents designed for new therapeutical approaches in atherosclerosis. Antioxid. Redox Signal. 14, 2093-2106.