ABSTRACT
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.
Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Atherosclerosis/prevention & control , Chelating Agents/pharmacology , Guaiacol/analogs & derivatives , Hydralazine/analogs & derivatives , Protein Carbonylation/drug effects , Animals , Cell Adhesion , Cells, Cultured , Chelating Agents/chemical synthesis , Chemokine CCL2/metabolism , Endothelial Cells , Enzyme Activation , Foam Cells/metabolism , Guaiacol/chemical synthesis , Guaiacol/pharmacology , Humans , Hydralazine/chemical synthesis , Hydralazine/pharmacology , Lipid Peroxidation/drug effects , Lipoproteins, LDL/chemistry , Lipoproteins, LDL/pharmacology , Male , Mice , Mice, Knockout , Oxidative Stress/drug effects , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , Proteasome Endopeptidase Complex/metabolism , Reactive Oxygen Species/metabolismABSTRACT
A novel series of hydrazones derived from syringaldehyde and their antioxidant properties have been explored. Several employed methods such as scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS(+)) radical cation expressed as Trolox equivalent antioxidant capacity (TEAC), inhibition of superoxide anion (O(2)(-)) generation and of human cell-mediated low-density lipoprotein oxidation (monitored by the formation of TBARS) exhibited their potent antioxidant properties. The carbonyl scavenger efficacy was also evaluated by measuring the ability to decrease the protein carbonyl content in cells challenged with oxidized LDL. In this report, we discuss about the synthesis of hydrazones and their dual biological role, antioxidant and carbonyl scavenger for further application in atherosclerosis.
