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The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury. / Xiao, Yang; Yim, Karen; Zhang, Hong et al.
In: Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy, Vol. 35, No. 4, 08.2021, p. 745-758.

Research output: Contribution to journal › Article › Academic › peer-review

Harvard

Xiao, Y, Yim, K, Zhang, H, Bakker, D, Nederlof, R, Smeitink, JAM, Renkema, H, Hollmann, MW, Weber, NC & Zuurbier, CJ 2021, 'The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury', Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy, vol. 35, no. 4, pp. 745-758. https://doi.org/10.1007/s10557-021-07189-9

APA

Xiao, Y., Yim, K., Zhang, H., Bakker, D., Nederlof, R., Smeitink, J. A. M., Renkema, H., Hollmann, M. W., Weber, N. C., & Zuurbier, C. J. (2021). The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy, 35(4), 745-758. https://doi.org/10.1007/s10557-021-07189-9

Vancouver

Xiao Y, Yim K, Zhang H, Bakker D, Nederlof R, Smeitink JAM et al. The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. 2021 Aug;35(4):745-758. Epub 2021. doi: 10.1007/s10557-021-07189-9

Author

Xiao, Yang ; Yim, Karen ; Zhang, Hong et al. / The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury. In: Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. 2021 ; Vol. 35, No. 4. pp. 745-758.

BibTeX

@article{fee26a862ace49a5be77f05a04a33349,
title = "The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury",
abstract = "Purpose: Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m{\textquoteright}s potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. Methods: Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. Results: During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. Conclusion: Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.",
keywords = "Antioxidant, Cytochrome c, Infarct size, Ischemia duration, Reperfusion injury",
author = "Yang Xiao and Karen Yim and Hong Zhang and Diane Bakker and Rianne Nederlof and Smeitink, {Jan A. M.} and Herma Renkema and Hollmann, {Markus W.} and Weber, {Nina C.} and Zuurbier, {Coert J.}",
note = "Funding Information: Khondrion provided the KH176m compound as a gift and partly funded animal costs. This work was partly supported by the Chinese Scholarship Council (201806270257). Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = aug,
doi = "10.1007/s10557-021-07189-9",
language = "English",
volume = "35",
pages = "745--758",
journal = "Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy",
issn = "0920-3206",
publisher = "Kluwer Academic Publishers",
number = "4",

}

RIS

TY - JOUR

T1 - The Redox Modulating Sonlicromanol Active Metabolite KH176m and the Antioxidant MPG Protect Against Short-Duration Cardiac Ischemia-Reperfusion Injury

AU - Xiao, Yang

AU - Yim, Karen

AU - Zhang, Hong

AU - Bakker, Diane

AU - Nederlof, Rianne

AU - Smeitink, Jan A. M.

AU - Renkema, Herma

AU - Hollmann, Markus W.

AU - Weber, Nina C.

AU - Zuurbier, Coert J.

N1 - Funding Information: Khondrion provided the KH176m compound as a gift and partly funded animal costs. This work was partly supported by the Chinese Scholarship Council (201806270257). Publisher Copyright: © 2021, The Author(s).

PY - 2021/8

Y1 - 2021/8

N2 - Purpose: Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m’s potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. Methods: Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. Results: During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. Conclusion: Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.

AB - Purpose: Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m’s potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. Methods: Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. Results: During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. Conclusion: Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.

KW - Antioxidant

KW - Cytochrome c

KW - Infarct size

KW - Ischemia duration

KW - Reperfusion injury

UR - http://www.scopus.com/inward/record.url?scp=85105462689&partnerID=8YFLogxK

U2 - 10.1007/s10557-021-07189-9

DO - 10.1007/s10557-021-07189-9

M3 - Article

C2 - 33914182

VL - 35

SP - 745

EP - 758

JO - Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy

JF - Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy

SN - 0920-3206

IS - 4

ER -

ID: 18254064