Chronic intermittent hypoxia induces cardiac hypertrophy by impairing autophagy through the adenosine 5′-monophosphate-activated protein kinase pathway
| Autor: | Sheng Xie, Yu Wang, Yan Deng, Jie Ren, Xiao Yuan, Huiguo Liu, Xue-ling Guo, Zhihua Wang, Jin Shang, Meng Jin, Die Zhu, Yue-ying Pan |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Adenosine monophosphate medicine.medical_specialty ATG5 Biophysics Apoptosis Cardiomegaly AMP-Activated Protein Kinases Biochemistry Autophagy-Related Protein 5 Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate Microscopy Electron Transmission Internal medicine Autophagy medicine Animals Phosphorylation Hypoxia Protein kinase A Molecular Biology Protein kinase B Sirolimus Calcineurin Myocardium Adenylate Kinase Hemodynamics AMPK NFAT Adenosine Rats 030104 developmental biology Endocrinology chemistry RNA Interference medicine.drug |
| Zdroj: | Archives of Biochemistry and Biophysics. 606:41-52 |
| ISSN: | 0003-9861 |
| DOI: | 10.1016/j.abb.2016.07.006 |
| Popis: | Autophagy is tightly regulated to maintain cardiac homeostasis. Impaired autophagy is closely associated with pathological cardiac hypertrophy. However, the relationship between autophagy and cardiac hypertrophy induced by chronic intermittent hypoxia (CIH) is not known. In the present study, we measured autophagy-related genes and autophagosomes during 10 weeks of CIH in rats, and 6 days in H9C2 cardiomyocytes, and showed that autophagy was impaired. This conclusion was confirmed by the autophagy flux assay. We detected significant hypertrophic changes in myocardium with impaired autophagy. Rapamycin, an autophagy enhancer, attenuated the cardiac hypertrophy induced by CIH. Moreover, silencing autophagy-related gene 5 (ATG5) exerted the opposite effect. The role of adenosine monophosphate-activated protein kinase (AMPK) in regulating autophagy under CIH was confirmed using AICAR to upregulate this enzyme and restore autophagy flux. Restoring autophagy by AICAR or rapamycin significantly reversed the hypertrophic changes in cardiomyocytes. To investigate the mechanism of autophagy impairment, we compared phospho (p)-AMPK, p-Akt, cathepsin D, and NFAT3 levels, along with calcineurin activity, between sham and CIH groups. CIH activated calcineurin, and inhibited AMPK and AMPK-mediated autophagy in an Akt- and NFAT3-independent manner. Collectively, these data demonstrated that impaired autophagy induced by CIH through the AMPK pathway contributed to cardiac hypertrophy. |
| Databáze: | OpenAIRE |
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