title: Carbonyl scavenger and antiatherogenic effects of hydrazine derivatives.
abstract: 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.
authors.affiliation: Inserm UMR-858, IFR-31, CHU Rangueil, Toulouse, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Galvani
authors.forename: Christelle
authors.initials: C
authors.lastname: Coatrieux
authors.forename: Meyer
authors.initials: M
authors.lastname: Elbaz
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Grazide
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Thiers
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.forename: Michel
authors.initials: M
authors.lastname: Baltas
authors.forename: Robert
authors.initials: R
authors.lastname: Salvayre
authors.forename: Anne
authors.initials: A
authors.lastname: Nègre-Salvayre
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008074:Lipoproteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D011817:Rabbits; D020298:U937 Cells
chemical_list: D001057:Apolipoproteins E; D016166:Free Radical Scavengers; D006834:Hydrazines; D008074:Lipoproteins