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

Sang Bing Ong, Won Hee Lee, Ning Yi Shao, Nur Izzah Ismail, Khairunnisa Katwadi, Mim Mim Lim, Xiu Yi Kwek, Nathaly Anto Michel, Jiajun Li, Jordan Newson, Soroush Tahmasebi, Jalees Rehman, Kazuki Kodo, Hye Ryoun Jang, Sang Ging Ong

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)597-610
Number of pages14
JournalStem cell reports
Volume12
Issue number3
DOIs
Publication statusPublished - 2019 Mar 5

Fingerprint

Induced Pluripotent Stem Cells
Calpain
Endothelial cells
Autophagy
Stem cells
Endothelial Cells
Medical problems
Reperfusion Injury
Blood Vessels
Mitochondria
Cysteine Proteases
Cell death
Hyperglycemia
Restoration
Reactive Oxygen Species
Cell Death
Adenosine Triphosphate
Chemical activation
Maintenance
Health

Keywords

  • autophagy
  • calpain
  • diabetes
  • endothelial dysfunction
  • iPSC
  • iPSC-ECs
  • ischemia-reperfusion injury
  • mitochondrial morphology

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy. / Ong, Sang Bing; Lee, Won Hee; Shao, Ning Yi; Ismail, Nur Izzah; Katwadi, Khairunnisa; Lim, Mim Mim; Kwek, Xiu Yi; Michel, Nathaly Anto; Li, Jiajun; Newson, Jordan; Tahmasebi, Soroush; Rehman, Jalees; Kodo, Kazuki; Jang, Hye Ryoun; Ong, Sang Ging.

In: Stem cell reports, Vol. 12, No. 3, 05.03.2019, p. 597-610.

Research output: Contribution to journalArticle

Ong, SB, Lee, WH, Shao, NY, Ismail, NI, Katwadi, K, Lim, MM, Kwek, XY, Michel, NA, Li, J, Newson, J, Tahmasebi, S, Rehman, J, Kodo, K, Jang, HR & Ong, SG 2019, 'Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy', Stem cell reports, vol. 12, no. 3, pp. 597-610. https://doi.org/10.1016/j.stemcr.2019.01.017
Ong, Sang Bing ; Lee, Won Hee ; Shao, Ning Yi ; Ismail, Nur Izzah ; Katwadi, Khairunnisa ; Lim, Mim Mim ; Kwek, Xiu Yi ; Michel, Nathaly Anto ; Li, Jiajun ; Newson, Jordan ; Tahmasebi, Soroush ; Rehman, Jalees ; Kodo, Kazuki ; Jang, Hye Ryoun ; Ong, Sang Ging. / Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy. In: Stem cell reports. 2019 ; Vol. 12, No. 3. pp. 597-610.
@article{b935c1a0c5a84786939a73f651606a8c,
title = "Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy",
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.",
keywords = "autophagy, calpain, diabetes, endothelial dysfunction, iPSC, iPSC-ECs, ischemia-reperfusion injury, mitochondrial morphology",
author = "Ong, {Sang Bing} and Lee, {Won Hee} and Shao, {Ning Yi} and Ismail, {Nur Izzah} and Khairunnisa Katwadi and Lim, {Mim Mim} and Kwek, {Xiu Yi} and Michel, {Nathaly Anto} and Jiajun Li and Jordan Newson and Soroush Tahmasebi and Jalees Rehman and Kazuki Kodo and Jang, {Hye Ryoun} and Ong, {Sang Ging}",
year = "2019",
month = "3",
day = "5",
doi = "10.1016/j.stemcr.2019.01.017",
language = "English",
volume = "12",
pages = "597--610",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy

AU - Ong, Sang Bing

AU - Lee, Won Hee

AU - Shao, Ning Yi

AU - Ismail, Nur Izzah

AU - Katwadi, Khairunnisa

AU - Lim, Mim Mim

AU - Kwek, Xiu Yi

AU - Michel, Nathaly Anto

AU - Li, Jiajun

AU - Newson, Jordan

AU - Tahmasebi, Soroush

AU - Rehman, Jalees

AU - Kodo, Kazuki

AU - Jang, Hye Ryoun

AU - Ong, Sang Ging

PY - 2019/3/5

Y1 - 2019/3/5

N2 - 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.

AB - 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.

KW - autophagy

KW - calpain

KW - diabetes

KW - endothelial dysfunction

KW - iPSC

KW - iPSC-ECs

KW - ischemia-reperfusion injury

KW - mitochondrial morphology

UR - http://www.scopus.com/inward/record.url?scp=85062077386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062077386&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2019.01.017

DO - 10.1016/j.stemcr.2019.01.017

M3 - Article

C2 - 30799273

AN - SCOPUS:85062077386

VL - 12

SP - 597

EP - 610

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 3

ER -