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Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling

  • Authors:
    • Guangyuan Gao
    • Weiwei Chen
    • Mengjie Yan
    • Jinsha Liu
    • Huiling Luo
    • Chang Wang
    • Ping Yang

  • View Affiliations

  • Published online on: November 13, 2019     https://doi.org/10.3892/ijmm.2019.4407
  • Pages: 195-209

  • Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The progressive loss of cardiomyocytes caused by cell death leads to cardiac dysfunction and heart failure (HF). Rapamycin has been shown to be cardioprotective in pressure‑overloaded and ischemic heart diseases by regulating the mechanistic target of rapamycin (mTOR) signaling network. However, the impact of rapamycin on cardiomyocyte death in chronic HF remains undetermined. Therefore, in the current study we addressed this issue using a rat myocardial infarction (MI)‑induced chronic HF model induced by ligating the coronary artery. Following surgery, rats were randomly divided into six groups, including the sham‑, vehicle‑ and rapamycin‑operated groups, at 8 or 12 weeks post‑MI. A period of 4 weeks after MI induction, the rats were treated with rapamycin (1.4 mg‑kg‑day) or vehicle for 4 weeks. Cardiac function was determined using echocardiography, the rats were subsequently euthanized and myocardial tissues were harvested for histological and biochemical analyses. In the cell culture experiments with H9c2 rat cardiomyocytes, apoptosis was induced using angiotensin II (100 nM; 24 h). Cardiomyocyte apoptosis and autophagy were assessed via measuring apoptosis‑ and autophagy‑associated proteins. The activities of mTOR complex 1 (mTORC1) and mTORC2 were evaluated using the phosphorylation states of ribosomal S6 protein and Akt, respectively. The activity of the endoplasmic reticulum (ER) stress pathway was determined using the levels of GRP78, caspase‑12, phospho‑JNK and DDIT3. Echocardiographic and histological measurements indicated that rapamycin treatment improved cardiac function and inhibited cardiac remodeling at 8 weeks post‑MI. Additionally, rapamycin prevented cardiomyocyte apoptosis and promoted autophagy at 8 weeks post‑MI. Rapamycin treatment for 4 weeks inhibited the mTOR and ER stress pathways. Furthermore, rapamycin prevented angiotensin II‑induced H9c2 cell apoptosis and promoted autophagy by inhibiting the mTORC1 and ER stress pathways. These results demonstrated that rapamycin reduced cardiomyocyte apoptosis and promoted cardiomyocyte autophagy, by regulating the crosstalk between the mTOR and ER stress pathways in chronic HF.
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January-2020
Volume 45 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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  • Ranked Medicine Research and Experimental
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  • CiteScore: 10.7
  • CiteScore Rank: Q1: #35/328 Biochemistry, Genetics and Molecular Biology
  • Source Normalized Impact per Paper (SNIP): 0.994
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Spandidos Publications style
Gao G, Chen W, Yan M, Liu J, Luo H, Wang C and Yang P: Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. Int J Mol Med 45: 195-209, 2020
APA
Gao, G., Chen, W., Yan, M., Liu, J., Luo, H., Wang, C., & Yang, P. (2020). Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. International Journal of Molecular Medicine, 45, 195-209. https://doi.org/10.3892/ijmm.2019.4407
MLA
Gao, G., Chen, W., Yan, M., Liu, J., Luo, H., Wang, C., Yang, P."Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling". International Journal of Molecular Medicine 45.1 (2020): 195-209.
Chicago
Gao, G., Chen, W., Yan, M., Liu, J., Luo, H., Wang, C., Yang, P."Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling". International Journal of Molecular Medicine 45, no. 1 (2020): 195-209. https://doi.org/10.3892/ijmm.2019.4407