Objective Iron regulatory hormone hepcidin is possible to be possibly involved in the physiological function of heart and pathogenesis of heart disease. The current paper reports the establishment of heart specific Hepc1 transgenic mice and analysis of the effect of Hepc1 on the development of dilated cardiomyopathy in the cTnT^R141W transgenic mice.

Methods The heart specific Hepc1 transgenic mice were generated by the method of microinjection and the target gene was under the control of α-MHC promoter. The expression level of the gene Hepc1 was determined by RT-PCR and slot blotting. The Hepc1×cTnT^R141W double transgenic mice were generated by breeding the Hepc1 transgenic mice with cTnT^R141W transgenic mice. The structural and functional changes of the transgenic heart were analysed with M-mode echocardiography. Survival data were recorded from 1 month to 7 months (the 1^st to the 7^th month) postnatally. The histological and subcellular changes were observed under light microscope and transmission electronic microscope. The accumulation of phos-ERK1/2 and ERK1/2 in wild type, Hepc1, cTnT^R141W and Hepc1×cTnT^R141W transgenic mice were determined by western blotting. Phos-ERK1/2 expression was also detected in H9c2 cell line, H9c2 cell line treated with desferrioxamine (50 μmol/l), H9c2 cell lines expressing Hepc1 protein and H9c2 cell lines expressing Hepc1 protein treated with ferric ammonium citrate (100 μmol/l).

Results 2 heart specific Hepc1 transgenic mice lines were established. Hepc1 transgenic mice demonstrated no signs of cardiomyopathy or lethality up to 7 months of age. The immature death rate was 18% before 7 months of age in the cTnT^R141W mice, while Hepc1×cTnT^R141W transgenic mice showed a lower immature death (10%). Hepc1×cTnT^R141W transgenic mice showed a smaller ventricular chamber, improved left ventricular systolic function, and ameliorated interstitial fibrosis, compared with (to) cTnT^R141W transgenic mice. ERK1/2 phosphorylation was strongly decreased in cTnT^R141W transgenic mice compared with (to) WT mice, while it was significantly increased in the Hepc1×cTnT^R141W transgenic mice compared with (to) cTnT^R141W transgenic mice. Both desferrioxamine, an iron chelator and the gene Hepc1 significantly increased ERK1/2 phosphorylation in H9c2 cell line.

Conclusions Hepc1 showed a marked improvement on (in) the pathologic phenotype of DCM in cTnT^R141W transgenic mice, in which ERK1/2 signal pathway may play an important role. Hepc1 may be a new target in the treatment of human dilated cardiomyopathy.