Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy
Lee, Won Hee
Ismail, Nur Izzah
Michel, Nathaly Anto
Jang, Hye Ryoun
AffiliationUniv Arizona, Dept Basic Med Sci
MetadataShow full item record
CitationOng, S. B., Lee, W. H., Shao, N. Y., Ismail, N. I., Katwadi, K., Lim, M. M., ... & Tahmasebi, S. (2019). Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy. Stem cell reports, 12(3), 597-610.
JournalSTEM CELL REPORTS
Rights© 2019 The Author(s).
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractThe relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult-simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.
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VersionFinal published version
SponsorsSingapore Ministry of Health's National Medical Research Council Open Fund-Young Individual Research Grant [NMRC/OFYIRG/0021/2016]; Khoo Postdoctoral Fellowship Award [Duke-NUS-KPFA/2016/0010]; Hitachi Scholarship Research Support Grant from the Hitachi Global Foundation, Japan [RS-13, H-1]; American Heart Association Scientist Development Grant [16SDG27560003]; Stanford Diabetes Research Center under NIH [P30DK116074]; Frontier Research Grant 2017 from the Frontier Science Research Cluster (FSRC), Universiti Malaya, Malaysia [FG021-17AFR]; NIH [R01HL126516, R00HL130416]; Samsung Biomedical Research Institute [OTC 1180261]; National Research Foundation of Korea [NRF-2016R1A2B4008235]
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