Berbamine postconditioning protects the heart from ischemia/reperfusion injury through modulation of autophagy
| Autor: | Jiliang Tan, Cai-Mei Zhang, Shenyan Liu, Huang-Tian Yang, Shanshan Gu, Yu-Kun Jiang, Yan-Jun Zheng, Xuxia Li, Ling Gao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Autophagosome Male Cancer Research Programmed cell death Cardiotonic Agents Immunology ATG5 Myocardial Reperfusion Injury 030204 cardiovascular system & hematology Pharmacology Biology Berbamine Benzylisoquinolines Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Phosphatidylinositol 3-Kinases 0302 clinical medicine medicine Autophagy Animals Myocytes Cardiac PI3K/AKT/mTOR pathway Cardioprotection Myocardium Cell Biology medicine.disease Rats 030104 developmental biology chemistry Original Article Beclin-1 Apoptosis Regulatory Proteins Reperfusion injury Microtubule-Associated Proteins Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Pretreatment of berbamine protects the heart from ischemia/reperfusion (I/R) injury. However it is unknown whether it has cardioprotection when given at the onset of reperfusion (postconditioning (PoC)), a protocol with more clinical impact. Autophagy is upregulated in I/R myocardium and exacerbates cardiomyocyte death during reperfusion. However, it is unknown whether the autophagy during reperfusion is regulated by berbamine. Here we investigated whether berbamine PoC (BMPoC) protects the heart through regulation of autophagy by analyzing the effects of BMPoC on infarct size and/or cell death, functional recovery and autophagy in perfused rat hearts and isolated cardiomyocytes subjected to I/R. Berbamine from 10 to 100 nM given during the first 5 min of reperfusion concentration-dependently improved post-ischemic myocardial function and attenuated cell death. Similar protections were observed in cardiomyocytes subjected to simulated I/R. Meanwhile, BMPoC prevented I/R-induced impairment of autophagosome processing in cardiomyocytes, characterized by increased LC3-II level and GFP-LC3 puncta, and decreased p62 degradation. Besides, lysosomal inhibitor chloroquine did not induce additional increase of LC3-II and P62 abundance after I/R but it reversed the effects of BMPoC in those parameters in cardiomyocytes, suggesting that I/R-impaired autophagic flux is restored by BMPoC. Moreover, I/R injury was accompanied by enhanced expression of Beclin 1, which was significantly inhibited by BMPoC. In vitro and in vivo adenovirus-mediated knockdown of Beclin 1 in myocardium and cardiomyocytes restored I/R-impaired autophagosome processing, associated with an improvement of post-ischemic recovery of myocardial contractile function and a reduction of cell death, but it did not have additive effects to BMPoC. Conversely, overexpression of Beclin 1 abolished the cardioprotection of BMPoC as did by overexpression of an essential autophagy gene Atg5. Furthermore, BMPoC-mediated cardioprotection was abolished by a specific Akt1/2 inhibitor A6730. Our results demonstrate that BMPoC confers cardioprotection by modulating autophagy during reperfusion through the activation of PI3K/Akt signaling pathway. |
| Databáze: | OpenAIRE |
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