Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences.
Labile iron in hemosiderotic plasma and tissue are sources of iron toxicity. We compared the iron chelators deferoxamine, deferiprone, and deferasirox as scavengers of labile iron in plasma and cardiomyocytes at therapeutic concentrations. This comprised chelation of labile plasma iron (LPI) in samples from thalassemia patients; extraction of total cellular iron; accessing labile iron accumulated in organelles and preventing formation of reactive-oxidant species; and restoring impaired cardiac contractility. Neonatal rat cardiomyocytes were used for monitoring chelator extraction of LCI (labile cell iron) as 59Fe; assessing in situ cell iron chelation by epifluorescence microscope imaging using novel fluorescent sensors for iron and reactive oxygen species (ROS) selectively targeted to organelles, and monitoring contractility by time-lapse microscopy. At plasma concentrations attained therapeutically, all 3 chelators eliminated LPI but the orally active chelators rapidly gained access to the LCI pools of cardiomyocytes, bound labile iron, attenuated ROS formation, extracted accumulated iron, and restored contractility impaired by iron overload. The effect of deferoxamine at therapeutically relevant concentrations was primarily by elimination of LPI. The rapid accessibility of the oral chelators deferasirox and deferiprone to intracellular labile iron compartments renders them potentially efficacious for protection from and possibly reversal of cardiac damage induced by iron overload.
Glickstein
Hava
H
Department of Biological Chemistry and Charles E. Smith Laboratory of Psychobiology, Institute of Life Sciences, Jerusalem, Israel.
El
Rinat Ben
RB
Link
Gabi
G
Breuer
William
W
Konijn
Abraham M
AM
Hershko
Chaim
C
Nick
Hanspeter
H
Cabantchik
Z Ioav
ZI
D000818:Animals; D000831:Animals, Newborn; D005452:Fluoresceins; D006321:Heart / Q000187:drug effects; D007501:Iron / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D005452:Fluoresceins; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; C083098:calcein green; D007501:Iron