Cardiac Hepcidin Expression Associates with Injury Independent of Iron

Abstract

Background: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content. Methods: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry. Results: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (β = 0.734, p < 0.001) and connective tissue growth factor (β = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups. Conclusions: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure.

Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology

“…[51] Another clue that hepcidin is increased in stress situations in the heart is its correlation with B-type natriuretic peptide, which has important cardioprotective functions during heart stress. 54,55 It is interesting to notice that, in models of heart hypoxia, cardiac hepcidin is upregulated, which is in contrast with downregulation of liver hepcidin seen during systemic hypoxia. 43 This might mean that hypoxia in the heart induces hepcidin upregulation as a protective mean in heart homeostasis.…”

“…However, this paradigm has been rivaled by studies from which we have learnt that cellular injury could be a more important factor than iron signaling in inducing cardiac hepcidin expression. 55 This would be why hepcidin expression is observed in remote myocardium in the setting of MI without an accompanied increase in ferritin depots. 53,55 On the other hand, it has to be mentioned that the lack of correlation between cardiac ferritin and hepcidin in rat models of cardiac injury is additionally complicated by the existence of sex differences in the regulation of iron metabolism.…”

“…55 This would be why hepcidin expression is observed in remote myocardium in the setting of MI without an accompanied increase in ferritin depots. 53,55 On the other hand, it has to be mentioned that the lack of correlation between cardiac ferritin and hepcidin in rat models of cardiac injury is additionally complicated by the existence of sex differences in the regulation of iron metabolism. 57 During cardiac injury, levels of BMP6 are upregulated in synchrony with levels of cardiac hepcidin, but there exists no correlation between these two parameters, as the one observed in the liver.…”

“…57 During cardiac injury, levels of BMP6 are upregulated in synchrony with levels of cardiac hepcidin, but there exists no correlation between these two parameters, as the one observed in the liver. 55 BMP6 is expressed in the heart and it is involved in cardiogenesis. 58 Its increase during cardiac injury has been proposed as an important downstream signal that is a part of a protective mechanism, which results in cardiac hypertrophy, increased vascularity, and decreased fibrosis.…”

Keeping heart homeostasis in check through the balance of iron metabolism

“…This is probably why knockdown of cardiac hepcidin is accompanied by dilated cardiomyopathy and low ejection fraction . Further evidence of the importance of cardiac hepcidin upregulation during cardiac injury is its correlation with other markers of cardiac injury such as brain natriuretic protein, atrial natriuretic protein and connective tissue growth factor . In addition, upregulation of cardiac hepcidin in remote myocardium also suggests that this protein is involved in controlling cardiac remodelling during injury, though this remains to be confirmed …”