Carbamylated erythropoietin attenuates cardiomyopathy via PI3K/Akt activation in rats with diabetic cardiomyopathy

Abstract

The aim of the present study was to investigate the protective effect of carbamylated erythropoietin (CEPO) against cardiomyopathy in high-fat, high-carbohydrate diet-fed rats with streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM). Healthy male Wistar rats were fed a high-fat, high-carbohydrate diet for four weeks, and then were injected with STZ twice (50 mg/kg, intraperitoneally). Once DCM was confirmed, the rats were divided randomly into the following groups: DCM without treatment, CEPO treatment at different dosages (500, 1,000 or 2,000 IU/kg) or recombinant human erythropoietin (rhEPO) treatment (1,000 IU/kg), for a four-week short intervention or an eight-week long intervention protocol. Healthy rats were used as normal controls. Venous blood samples were drawn for routine hematological examinations, and heart tissues were collected for histological analysis, as well as the determination of myocardial apoptosis and phosphatidylinositol-3-kinase (PI3K)/Akt signaling. CEPO treatment had no significant effect on the erythrocyte or hemoglobin levels in the rats with DCM; however, it reduced myocardial cell apoptosis in the rats and protected the cellular ultrastructure. In addition, CEPO treatment inhibited caspase-3 and increased Bcl-xl protein expression (P<0.05). It also increased PI3K (p85) and Akt1 expression at the mRNA and protein levels in the hearts of the rats with DCM, with a dose-response relationship. An eight-week treatment using CEPO, in comparison with a four-week protocol, marginally increased PI3K (p85) and Akt1 expression, and did not demonstrate significant benefit. The study indicated that CEPO protects against DCM, without markedly affecting erythropoiesis, and that the activation of PI3K/Akt may be a key mechanism in the protection conferred by CEPO.

Retracted: Upregulated microRNA‐132 rescues cardiac fibrosis and restores cardiocyte proliferation in dilated cardiomyopathy through the phosphatase and tensin homolog–mediated PI3K/Akt signal transduction pathway

“…For example, Wu et al 43 suggested that resveratrol exerted a protective effect on neonatal rats with DCM by inhibiting myocyte apoptosis through the PI3K/Akt/FoxO3a signal transduction pathway. Similarly, He et al 44 pointed out that carbamylated erythropoietin is capable of attenuating cardiomyopathy by activating the PI3K/Akt signal transduction pathway in rat models of DCM. Recently, it has been reported that the PI3K/Akt signal transduction pathway played a significant role in the regulation of cardiocyte metabolism.…”

The role of PI3-K/Akt signal pathway in the antagonist effect of CEPO on CHF rats

“…Results of western blotting assay showed that CEPO could elevate the level of pAkt, which was inhibited by treatment of LY, suggesting that CEPO can ameliorate the heart function of CHF rats through PI3-K/Akt signal pathway. Results in this study agreed with those of He et al ( 23 ).…”

Effect of carbamylated erythropoietin on neuronal apoptosis in fetal rats during intrauterine hypoxic-ischemic encephalopathy

“…Nevertheless, the present study showed that CEPO significantly downregulated the CC3 expression at similar time points compared to the I/R group. The effect of CEPO on CC3 was similar to the findings of previous studies using different animal models [27, 28]. These findings suggest that CEPO might sufficiently provide early beneficial effects for intrauterine HIE.…”