Polycystin 2 Plays an Essential Role in Glucose Starvation Induced Autophagy in Human Embryonic Stem Cell Derived Cardiomyocytes
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摘要Introduction: Autophagy is a process essential for cell survival under stress condition. The patients with autosomal dominant polycystic kidney disease (ADPKD), which is caused by polycystin1 (PKD1) or polycystin 2 (PKD2) mutation, displayed cardiovascular abnormalities and dysregulation in autophagy. However, it is unclear whether PKD2 plays a role in autophagy. In the present study, we explored the functional role of PKD2 in autophagy and apoptosis in human embryonic stem cell derived cardiomyocytes (hESC-CMs).
Methods and Results: hESC-CMs transduced with adenoviral-based PKD2-shRNAs (Ad-PKD2-shRNAs) were cultured with normal or glucose-free medium for 3 hr. Autophagy was upregulated in hESC-CMs subjected to glucose starvation, as indicated by increased LC3-II level in immunoblots and increased autophagosome and autolysosome formation under fluorescence confocal microscopy. Knockdown of PKD2 by Ad-PKD2-shRNAs reduced the autophagic flux under glucose starvation condition, which was accompanied by increased apoptosis. In Ca2+ measurement, Ad-PKD2-shRNAs reduced the magnitude of spontaneous Ca2+ oscillations and impaired the isoprenaline-stimulated Ca2+ oscillations. Furthermore, co-immunoprecipitation and in situ proximity ligation assay demonstrated an increased physical interaction of PKD2 with RyR2 under glucose starvation condition. Furthermore, PKD2-shRNA substantially attenuated the starvation-induced AMPK activation and mTOR inactivation in hESC-CMs.
Conclusion: The present study demonstrates that PKD2 functions to facilitate autophagy under glucose starvation condition, thereby protect cardiomyocytes from apoptotic cell death. The mechanism may involve PKD2 interaction with RyR2 to alter the store Ca2+ release resulting in alteration of autophagy and apoptosis. This scheme may have important pathophysiological relevance in ischemic heart diseases and ADPKD.
著者Jun LU, Liwen JIANG, Camie W. CHAN, Kennis TSE, Wendy KEUNG, Ronald A LI, Xiaoqiang YAO
會議名稱The 6th International Ion Channel Conference

上次更新時間 2018-18-01 於 11:20