Endoplasmic reticulum stress involved in heart and liver injury in iron-loaded rats.
1. Iron overload contributes to the pathogenesis of various diseases and directly induces tissue injury. In the present study, we investigated the relationship between heart and liver injury induced by iron overload and cellular endoplasmic reticulum (ER) stress to explore the molecular mechanism of iron overload-induced cellular injury. 2. Iron overload in rats was generated by intraperitoneal injection of iron-dextran chronically (30 mg/kg per day for 9 weeks) or acutely (300 mg/kg once). Tissue injury was assessed by determining serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, as well as malondialdehyde (MDA) content in the heart and liver. The ER stress response was analysed by expression of glucose-response protein 78 (GRP78) and activation of caspase 12. 3. In chronic iron-loaded rats, iron levels in the heart and liver were higher, by approximately 2- and 7.8-fold, respectively (P < 0.01), compared with control. Serum LDH, ALT and AST activity, as well as MDA content, GRP78 expression and caspase 12 activity in the heart and liver, were upregulated in chronically iron-loaded rats. In acute iron-loaded rats, iron content in the heart and liver was 51% and 63% higher than in controls (both P < 0.01). Serum LDH, ALT and AST activity, MDA content in the heart and liver and levels of ER stress markers were all increased in acute iron-loaded rats. N-Acetylcysteine (150 mg/kg, s.c.) lowered the levels of these parameters in acute iron-loaded rats. 4. The results of the present study indicate that ER stress may play an important role in iron-induced tissue injury and that reactive oxygen species may mediate the ER stress response in the pathogenesis of iron-overload cellular injury.
Lou
Li-Xia
LX
Institute of Cardiovascular Diseases, Peking University First Hospital, Beijing, China.
Geng
Bin
B
Chen
Yu
Y
Yu
Fang
F
Zhao
Jing
J
Tang
Chao-Shu
CS
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007501:Iron / Q000378:metabolism / Q000633:toxicity*; D019190:Iron Overload / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*
D007501:Iron