Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury.
Heme oxygenase-1 (HO-1) is induced under a variety of pro-oxidant conditions such as those associated with ischemia-reperfusion injury (IRI) of transplanted organs. HO-1 cleaves the heme porphyrin ring releasing Fe2+, which induces the expression of the Fe2+ sequestering protein ferritin. By limiting the ability of Fe2+ to participate in the generation of free radicals through the Fenton reaction, ferritin acts as an anti-oxidant. We have previously shown that HO-1 protects transplanted organs from IRI. We have linked this protective effect with the anti-apoptotic action of HO-1. Whether the iron-binding properties of ferritin contributed to the protective effect of HO-1 was not clear. We now report that recombinant adenovirus mediated overexpression of the ferritin heavy chain (H-ferritin) gene protects rat livers from IRI and prevents hepatocellular damage upon transplantation into syngeneic recipients. The protective effect of H-ferritin is associated with the inhibition of endothelial cell and hepatocyte apoptosis in vivo. H-ferritin protects cultured endothelial cells from apoptosis induced by a variety of stimuli. These findings unveil the anti-apoptotic function of H-ferritin and suggest that H-ferritin can be used in a therapeutic manner to prevent liver IRI and thus maximize the organ donor pool used for transplantation.
Berberat
P O
PO
Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Katori
M
M
Kaczmarek
E
E
Anselmo
D
D
Lassman
C
C
Ke
B
B
Shen
X
X
Busuttil
R W
RW
Yamashita
Kenichiro
K
Csizmadia
Eva
E
Tyagi
Shivraj
S
Otterbein
Leo E
LE
Brouard
S
S
Tobiasch
E
E
Bach
F H
FH
Kupiec-Weglinski
J W
JW
Soares
M P
MP
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002417:Cattle; D019610:Cytoprotection; D004727:Endothelium / Q000166:cytology; D005293:Ferritins / Q000235:genetics* / Q000502:physiology; D005822:Genetic Vectors; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D016031:Liver Transplantation / Q000009:adverse effects; D051379:Mice; D008954:Models, Biological; D051381:Rats; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
D005293:Ferritins