Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy

Stem Cell Reports
Sang-Bing OngSang-Ging Ong

Abstract

The 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.

Citations

Mar 21, 2020·Journal of Cardiovascular Pharmacology·Ken ChenDachun Yang
Sep 12, 2020·International Journal of Molecular Sciences·Konstantin N BelosludtsevMikhail V Dubinin
May 31, 2019·International Journal of Molecular Sciences·Nina C WeberHemal H Patel
Dec 11, 2019·Journal of Toxicology and Environmental Health. Part a·Yue YangZhen Ding
Jan 30, 2021·Frontiers in Cell and Developmental Biology·Hye Ryoun JangYoon-Goo Kim
Oct 13, 2020·Mechanisms of Ageing and Development·Jeremy ThompsonQun Chen
Mar 5, 2021·Frontiers in Cardiovascular Medicine·Crystal C KennedyGeorge A Truskey
Mar 7, 2021·International Journal of Molecular Sciences·Sophie RomeSoazig Le Lay

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Datasets Mentioned

BETA
GSE123699

Methods Mentioned

BETA
flow cytometry
fluorescence microscopy

Software Mentioned

ImageJ
Bioconductor
GeneAnswers
Ensembl
Fiji

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