Carbonyl scavenger and antiatherogenic effects of hydrazine derivatives.
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.
Galvani
Sylvain
S
Inserm UMR-858, IFR-31, CHU Rangueil, Toulouse, France.
Coatrieux
Christelle
C
Elbaz
Meyer
M
Grazide
Marie-Hélène
MH
Thiers
Jean-Claude
JC
Parini
Angelo
A
Uchida
Koji
K
Kamar
Nassim
N
Rostaing
Lionel
L
Baltas
Michel
M
Salvayre
Robert
R
Nègre-Salvayre
Anne
A
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
D001057:Apolipoproteins E; D016166:Free Radical Scavengers; D006834:Hydrazines; D008074:Lipoproteins