HFE mutation and dietary iron content interact to increase ischemia/reperfusion injury of the heart in mice.
Hereditary hemochromatosis is an inherited pathological condition characterized by iron overload in several vital organs including heart. To increase our understanding of the underlying pathogenic mechanisms of hereditary hemochromatosis, we used a HFE gene knockout mouse model that replicates hereditary hemochromatosis. A group of mice with no copies of HFE gene and corresponding wild-type mice were maintained either on low-iron (30 ppm) or high-iron (300 ppm) diet since birth. The results of our study revealed that HFE gene knockout mouse hearts were susceptible to ischemia-reperfusion injury as evidenced by increased postischemic ventricular dysfunction, increased myocardial infarct size and cardiomyocyte apoptosis compared with wild-type control hearts. The degree of injury increased in the hearts of the mice fed high-iron diet. The hearts of the HFE knockout mice showed increased iron deposition, increased content of reactive oxygen species (ROS) as evidenced by the increased formation of malondialdehyde, and reduced antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase. The results suggest that increased amount of ROS and reduced antioxidant reserve secondary to iron overloading may be instrumental for the susceptibility of the HFE gene knockout mice to cardiac injury.
Department of Surgery, University of Connecticut School of Medicine, Farmington, Conn 06030-1110, USA.
Tibor
T
Turoczi
Li
L
Jun
Gerald
G
Cordis
James E
JE
Morris
Nilanjana
N
Maulik
Richard G
RG
Stevens
Dipak K
DK
Das
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D004032:Diet; D006432:Hemochromatosis / Q000150:complications*; D000071020:Hemochromatosis Protein; D006439:Hemodynamics; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007501:Iron / Q000008:administration & dosage / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D007501:Iron