Antiatherogenic effect of bisvanillyl-hydralazone, a new hydralazine derivative with antioxidant, carbonyl scavenger, and antiapoptotic properties.
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.
Biochimie, INSERM U858, Team "Atherosclerosis," Toulouse, France.
Benaissa
B
Bouguerne
Nadji
N
Belkheiri
Florence
F
Bedos-Belval
Cécile
C
Vindis
Koji
K
Uchida
Hubert
H
Duran
Marie-Hélène
MH
Grazide
Michel
M
Baltas
Robert
R
Salvayre
Anne
A
Nègre-Salvayre
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000517:prevention & control*; D002448:Cell Adhesion; D002478:Cells, Cultured; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000378:metabolism; D042783:Endothelial Cells; D004789:Enzyme Activation; D005487:Foam Cells / Q000378:metabolism; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006830:Hydralazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; C111835:CCL2 protein, human; D002614:Chelating Agents; D018932:Chemokine CCL2; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C562068:bisvanillyl-hydralazone; C099252:oxidized low density lipoprotein; D006830:Hydralazine; D006139:Guaiacol; D046988:Proteasome Endopeptidase Complex