title: Silencing of hepcidin enforces the apoptosis in iron-induced human cardiomyocytes.
abstract: BACKGROUND
  Iron is essential not only for erythropoisis but also for several bioenergetics' processes in myocardium. Hepcidin is a well-known regulator of iron homeostasis. Recently, researchers identified low hepcidin was independently associated with increased 3-year mortality among systolic heart failure patients. In addition, our previous in vivo study revealed that the left ventricular mass index increased in chronic kidney disease patients with lower serum hepcidin. We hypothesize that hepcidin interacts with the apoptotic pathway of cardiomyocytes during oxidative stress conditions.
  
  
  METHODS
  To test this hypothesis, human cardiomyocytes were cultured and treated with ferrous iron. The possible underlying signaling pathways of cardiotoxicity were examined following knockdown studies using siRNAs of hepcidin (siRNA1 was used as a negative control and siRNA2 was used to silence hepcidin).
  
  
  RESULTS
  We found that ferrous iron induces apoptosis in human cardiomyocytes in a dose-dependent manner. This iron-induced apoptosis was linked to enhanced caspase 8, reduced Bcl-2, Bcl-xL, phosphorylated Akt and GATA-4. Hepcidin levels increased in human cardiomyocytes pretreated with ferrous iron and returned to non-iron treated levels following siRNA2 transfection. In iron pretreated cardiomyocytes, the siRNA2 transfection further increased caspase 8 expression and decreased the expression of GATA-4, Bcl-2, Bcl-xL and phosphorylated Akt than iron pretreatment alone, but caspase 9 levels remained unchanged.
  
  
  CONCLUSIONS
  Our findings suggest that hepcidin can rescue human cardiomyocytes from iron-induced apoptosis through the regulation of GATA-4/Bcl-2 and the extrinsic apoptotic pathway.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao St., Changhua 500, Taiwan.|Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Yao-Peng
authors.initials: YP
authors.lastname: Hsieh
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Division of Pediatric Nephrology, China Medical University Hospital, Changhua, Taiwan.
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Clinical Immunological Center, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.|Program for Aging, China Medical University, Taichung, Taiwan.
authors.forename: Ching-Yuang
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao St., Changhua 500, Taiwan.|Program for Aging, China Medical University, Taichung, Taiwan.|School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chia-Chu
authors.initials: CC
authors.lastname: Chang