TY - JOUR
T1 - Mechanistic and Kinetic Insights into Cellular Uptake of Biomimetic Dinitrosyl Iron Complexes and Intracellular Delivery of NO for Activation of Cytoprotective HO-1
AU - Chiu, Han
AU - Chau Fang, Anyelina
AU - Chen, Yi Hong
AU - Koi, Ru Xin
AU - Yu, Kai Ching
AU - Hsieh, Li Hung
AU - Shyu, Yueh Ming
AU - Amer, Tarik Abdelkareem Mostafa
AU - Hsueh, Yi Jen
AU - Tsao, Yu Ting
AU - Shen, Yang Jin
AU - Wang, Yun Ming
AU - Chen, Hung Chi
AU - Lu, Yu Jen
AU - Huang, Chieh Cheng
AU - Lu, Tsai Te
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society
PY - 2024/4/22
Y1 - 2024/4/22
N2 - Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(μ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(μ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n−/[(NO)2Fe(SR)(SCys-protein)]n− occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.
AB - Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(μ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(μ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n−/[(NO)2Fe(SR)(SCys-protein)]n− occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.
KW - corneal endothelial cell
KW - dinitrosyl iron complex
KW - heme oxygenase-1
KW - mesenchymal stem cell
KW - nitric oxide
KW - regenerative medicine
KW - thiol-mediated uptake
UR - http://www.scopus.com/inward/record.url?scp=85189091887&partnerID=8YFLogxK
U2 - 10.1021/jacsau.4c00064
DO - 10.1021/jacsau.4c00064
M3 - Article
AN - SCOPUS:85189091887
SN - 2691-3704
VL - 4
SP - 1550
EP - 1569
JO - JACS Au
JF - JACS Au
IS - 4
ER -