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Erythropoietin Attenuates Cardiac Dysfunction in Rats by Inhibiting Endoplasmic Reticulum Stress-Induced Diabetic Cardiomyopathy

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Abstract

Purpose

Enhanced endoplasmic reticulum (ER) stress and down-regulated SERCA2a expression play crucial roles in diabetes. We aimed to verify whether erythropoietin (EPO) attenuates cardiac dysfunction by suppressing ER stress in diabetic rats.

Methods

Forty male SD rats were randomly divided into four groups: control, EPO-treated control, vehicle-treated diabetic, and EPO-treated diabetic groups. The animals in the EPO-treated control and diabetic groups were administered recombinant human EPO (1000 U/kg body weight) once per week for 12 weeks. RT-PCR and Western blotting assays were performed to detect the expression of 78-kDa glucose-regulated protein precursor (GRP78) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). We cultured neonatal rat cardiomyocytes and investigated the protective effects of EPO against high glucose (HG)-induced apoptosis. Intracellular calcium levels were measured through confocal microscopy.

Results

We observed increased myocardial GRP78 expression and decreased myocardial SERCA2a expression in diabetic rats. EPO prevented the changes in GRP78, SERCA2a expression and cardiac dysfunction in diabetic rats. The levels of GRP78 protein were significantly reduced in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (GRP78 protein 0.09 ± 0.03 vs. 0.54 ± 0.04, P < 0.01). The levels of the SERCA2a proteins were significantly increased in EPO-treated diabetic rats compared with vehicle-treated diabetic rats (SERCA2a protein 0.60 ± 0.05 vs. 0.13 ± 0.04, P < 0.01). A reduction in apoptosis was observed in the cardiomyocytes treated with 20 U/mL EPO compared with the cardiomyocytes cultured under HG conditions (apoptosis rate 18.9 ± 1.94 vs. 37.9 ± 1.59%, P < 0.01).

Conclusions

This study demonstrates that EPO treatment improved the parameters of cardiac function following HG-induced injury by suppressing ER stress and inducing SERCA2a expression.

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References

  1. Lacombe VA, Viatchenko-Karpinski S, Terentyev D, et al. Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1787–97.

    Article  CAS  Google Scholar 

  2. Basu R, Oudit GY, Wang X, et al. Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol. 2009;297:H2096–108.

    Article  CAS  Google Scholar 

  3. Kranstuber AL, Del Rio C, Biesiadecki BJ, et al. Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling. Front Physiol. 2012;3:292.

    Article  Google Scholar 

  4. Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev. 2013;18:149–66.

    Article  Google Scholar 

  5. Takada A, Miki T, Kuno A, et al. Role of ER stress in ventricular contractile dysfunction in type 2 diabetes. PLoS One. 2012;7:e39893.

    Article  CAS  Google Scholar 

  6. Weng S, Zhu X, Jin Y, Wang T, Huang H. Protective effect of erythropoietin on myocardial infarction in rats by inhibition of caspase-12 expression. Exp Ther Med. 2011;2:833–6.

    Article  CAS  Google Scholar 

  7. Zhao H, Wang R, Wu X, et al. Erythropoietin delivered via intra-arterial infusion reduces endoplasmic reticulum stress in brain microvessels of rats following cerebral ischemia and reperfusion. J NeuroImmune Pharmacol. 2015;10:153–61.

    Article  Google Scholar 

  8. Kong D, Zhuo L, Gao C, et al. Erythropoietin protects against cisplatin-induced nephrotoxicity by attenuating endoplasmic reticulum stress-induced apoptosis. J Nephrol. 2013;26:219–27.

    Article  CAS  Google Scholar 

  9. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412.

    Article  Google Scholar 

  10. Yin M, Sillje HH, Meissner M, van Gilst WH, de Boer RA. Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure. Cardiovasc Diabetol. 2011;10:85.

    Article  CAS  Google Scholar 

  11. Hascall VC, Calabro A, Midura RJ, Yanagishita M. Isolation and characterization of proteoglycans. Methods Enzymol. 1994;230:390–417.

    Article  CAS  Google Scholar 

  12. Zhao Y, Yan Y, Zhao Z, Li S, Yin J. The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice. Brain Res Bull. 2015;111:27–35.

    Article  CAS  Google Scholar 

  13. Yu H, Zhen J, Yang Y, Gu J, Wu S, Liu Q. Ginsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat model. J Cell Mol Med. 2016;20:623–31.

    Article  CAS  Google Scholar 

  14. Xu J, Zhou Q, Xu W, Cai L. Endoplasmic reticulum stress and diabetic cardiomyopathy. Exp Diabetes Res. 2012;2012:827971.

    Article  Google Scholar 

  15. Shi FH, Cheng YS, Dai DZ, Peng HJ, Cong XD, Dai Y. Depressed calcium-handling proteins due to endoplasmic reticulum stress and apoptosis in the diabetic heart are attenuated by argirein. Naunyn Schmiedeberg's Arch Pharmacol. 2013;386:521–31.

    Article  CAS  Google Scholar 

  16. Kain V, Kumar S, Sitasawad SL. Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis. Cardiovasc Diabetol. 2011;10:97.

    Article  CAS  Google Scholar 

  17. Lu J, Yao YY, Dai QM, et al. Erythropoietin attenuates cardiac dysfunction by increasing myocardial angiogenesis and inhibiting interstitial fibrosis in diabetic rats. Cardiovasc Diabetol. 2012;11:105.

    Article  CAS  Google Scholar 

  18. Hong Z, Hong H, Chen H, Wang Z, Hong D. Protective effects of erythropoietin in experimental spinal cord injury by reducing the C/EBP-homologous protein expression. Neurol Res. 2012;34:85–90.

    Article  CAS  Google Scholar 

  19. Cha JR, Kim SJ, Heo TH. Protective effect of recombinant human erythropoietin in type II Gaucher disease patient cells by scavenging endoplasmic reticulum stress. Biomed Pharmacother. 2011;65:364–8.

    Article  CAS  Google Scholar 

  20. Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation. 2011;124:2903–8.

    Article  CAS  Google Scholar 

  21. Frietsch T, Maurer MH, Vogel J, Gassmann M, Kuschinsky W, Waschke KF. Reduced cerebral blood flow but elevated cerebral glucose metabolic rate in erythropoietin overexpressing transgenic mice with excessive erythrocytosis. J Cereb Blood Flow Metab. 2007;27:469–76.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department and Institute of Cardiology, Zhongda Hospital, Medical School of Southeast University, No. 87 Dingjiaqiao Street, Nanjing, 210009, Jiangsu, People’s Republic of China

    Jing Lu, Qi-ming Dai, Gen-shan Ma, Yue-hong Zhu, Bing Chen, Bing Li & Yu-yu Yao

Authors
  1. Jing Lu
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  2. Qi-ming Dai
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  3. Gen-shan Ma
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  4. Yue-hong Zhu
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  5. Bing Chen
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  6. Bing Li
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  7. Yu-yu Yao
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Corresponding author

Correspondence to Yu-yu Yao.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants and/or Animals

Forty male Sprague,Dawley rats were utilized in this study.

Informed Consent

None.

Funding

This study was supported by a grant from the National Natural Science Foundation of China (81300249 to Jing Lu, 81470401 to Yuyu Yao).

Ethical Approval

All procedures described in the present study were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Care of Experimental Animals Committee of Southeast University (approval ID: SYXK-2014.1923).

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Lu, J., Dai, Qm., Ma, Gs. et al. Erythropoietin Attenuates Cardiac Dysfunction in Rats by Inhibiting Endoplasmic Reticulum Stress-Induced Diabetic Cardiomyopathy. Cardiovasc Drugs Ther 31, 367–379 (2017). https://doi.org/10.1007/s10557-017-6742-1

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  • DOI: https://doi.org/10.1007/s10557-017-6742-1

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