SIH--a novel lipophilic iron chelator--protects H9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death.
Recent evidence suggests that oxidative stress is a common denominator in many aspects of cardiovascular pathogenesis. Free cellular iron plays a crucial catalytic role in the formation of highly toxic hydroxyl radicals, and thereby it may aggravate the contribution of oxidative stress to cardiovascular disease. Therefore, iron chelation may be an effective therapeutic approach, but the progress in this area is hindered by the lack of effective agents. In this study, using the rat heart myoblast-derived cell line H9c2, we aimed to investigate whether the novel lipophilic iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) protects the cells against hydrogen peroxide (H2O2)-induced cytotoxicity. Exposure of cells to 100 micromol/l H2O2 has within 4 h induced a complete dissipation of their mitochondrial membrane potential (DeltaPsim). Co-treatment with SIH dose-dependently reduced (EC50=0.8 micromol/l) or even completely abolished (3 micromol/l) this collapse. Furthermore, the latter SIH concentration was capable to fully prevent alterations in cell morphology, and inhibited both apoptosis (annexin-V staining, nuclear chromatin shrinkage, TUNEL positivity) and necrosis (propidium iodide staining), even 24 h after the H2O2 exposure. In comparison, deferoxamin (a commercially available hydrophilic iron chelator used in clinical practice and most previous studies) was cytoprotective only at three-order higher and clinically unachievable concentrations (EC50=1300 micromol/l). Thus, in this study, we present iron chelation as a very powerful tool by which oxidative stress-induced myocardial damage can be prevented.
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. simunekt@faf.cuni.cz
Tomás
T
Simůnek
Christa
C
Boer
R Arthur
RA
Bouwman
Ronald
R
Vlasblom
Amanda M G
AM
Versteilen
Martin
M
Sterba
Vladimír
V
Gersl
Radomír
R
Hrdina
Premysl
P
Ponka
Jaap J
JJ
de Lange
Walter J
WJ
Paulus
René J P
RJ
Musters
D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D048430:Cell Shape; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032386:Myoblasts, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats
D000447:Aldehydes; D006835:Hydrazones; D007502:Iron Chelating Agents; C413684:salicylaldehyde isonicotinoyl hydrazone; D006861:Hydrogen Peroxide