Histochrome attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis-induced cardiomyocyte death

Ji Won Hwang; Jae Hyun Park; Bong Woo Park; Hyeok Kim; Jin Ju Kim; Woo Sup Sim; Natalia P. Mishchenko; Sergey A. Fedoreyev; Elena A. Vasileva; Kiwon Ban; Hun Jun Park; Sang Hong Baek

doi:10.3390/antiox10101624

Histochrome attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis-induced cardiomyocyte death

Ji Won Hwang, Jae Hyun Park, Bong Woo Park, Hyeok Kim, Jin Ju Kim, Woo Sup Sim, Natalia P. Mishchenko, Sergey A. Fedoreyev, Elena A. Vasileva, Kiwon Ban, Hun Jun Park, Sang Hong Baek

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

50 Scopus citations

Abstract

Reactive oxygen species (ROS) and intracellular iron levels are critical modulators of lipid peroxidation that trigger iron-dependent non-apoptotic ferroptosis in myocardial ischemia-reperfusion (I/R) injury. Histochrome (HC), with a potent antioxidant moiety and iron-chelating capacity, is now available in clinical practice. However, limited data are available about the protective effects of HC on ferroptotic cell death in myocardial I/R injury. In this study, we investigated whether the intravenous administration of HC (1 mg/kg) prior to reperfusion could decrease myocardial damage by reducing ferroptosis. Rats undergoing 60 min of ischemia and reperfusion were randomly divided into three groups as follows: (1) Sham, (2) I/R control, and (3) I/R + HC. Serial echocar-diography up to four weeks after I/R injury showed that intravenous injection of HC significantly improved cardiac function compared to the I/R controls. In addition, the hearts of rats who received intravenous injection of HC exhibited significantly lower cardiac fibrosis and higher capillary density. HC treatment decreased intracellular and mitochondrial ROS levels by upregulating the expression of nuclear factor erythroid 2-related factor (Nrf2) and its downstream genes. HC also inhibited erastin-and RSL3-induced ferroptosis in rat neonatal cardiomyocytes by maintaining the intracellular glutathione level and through upregulated activity of glutathione peroxidase 4. These findings suggest that early intervention with HC before reperfusion rescued myocardium from I/R injury by preventing ferroptotic cell death. Therefore, HC is a promising therapeutic option to provide secondary cardioprotection in patients who undergo coronary reperfusion therapy.

Original language	English
Article number	1624
Journal	Antioxidants
Volume	10
Issue number	10
DOIs	https://doi.org/10.3390/antiox10101624
State	Published - Oct 2021

Bibliographical note

Funding Information:
Funding: This work has supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No.2018R1A2B600638013 to S.-H.B. and No.2021R1A4A303187511 to H.-J.P.).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Anti-ferroptosis
Cardioprotection
Histochrome
Iron-chelating
Ischemia-reperfusion injury

Access to Document

10.3390/antiox10101624

Cite this

@article{92f2ddad706b4547b355b9ff0211a362,

title = "Histochrome attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis-induced cardiomyocyte death",

abstract = "Reactive oxygen species (ROS) and intracellular iron levels are critical modulators of lipid peroxidation that trigger iron-dependent non-apoptotic ferroptosis in myocardial ischemia-reperfusion (I/R) injury. Histochrome (HC), with a potent antioxidant moiety and iron-chelating capacity, is now available in clinical practice. However, limited data are available about the protective effects of HC on ferroptotic cell death in myocardial I/R injury. In this study, we investigated whether the intravenous administration of HC (1 mg/kg) prior to reperfusion could decrease myocardial damage by reducing ferroptosis. Rats undergoing 60 min of ischemia and reperfusion were randomly divided into three groups as follows: (1) Sham, (2) I/R control, and (3) I/R + HC. Serial echocar-diography up to four weeks after I/R injury showed that intravenous injection of HC significantly improved cardiac function compared to the I/R controls. In addition, the hearts of rats who received intravenous injection of HC exhibited significantly lower cardiac fibrosis and higher capillary density. HC treatment decreased intracellular and mitochondrial ROS levels by upregulating the expression of nuclear factor erythroid 2-related factor (Nrf2) and its downstream genes. HC also inhibited erastin-and RSL3-induced ferroptosis in rat neonatal cardiomyocytes by maintaining the intracellular glutathione level and through upregulated activity of glutathione peroxidase 4. These findings suggest that early intervention with HC before reperfusion rescued myocardium from I/R injury by preventing ferroptotic cell death. Therefore, HC is a promising therapeutic option to provide secondary cardioprotection in patients who undergo coronary reperfusion therapy.",

keywords = "Anti-ferroptosis, Cardioprotection, Histochrome, Iron-chelating, Ischemia-reperfusion injury",

author = "Hwang, {Ji Won} and Park, {Jae Hyun} and Park, {Bong Woo} and Hyeok Kim and Kim, {Jin Ju} and Sim, {Woo Sup} and Mishchenko, {Natalia P.} and Fedoreyev, {Sergey A.} and Vasileva, {Elena A.} and Kiwon Ban and Park, {Hun Jun} and Baek, {Sang Hong}",

note = "Funding Information: Funding: This work has supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No.2018R1A2B600638013 to S.-H.B. and No.2021R1A4A303187511 to H.-J.P.). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = oct,

doi = "10.3390/antiox10101624",

language = "English",

volume = "10",

journal = "Antioxidants",

issn = "2076-3921",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "10",

}

TY - JOUR

T1 - Histochrome attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis-induced cardiomyocyte death

AU - Hwang, Ji Won

AU - Park, Jae Hyun

AU - Park, Bong Woo

AU - Kim, Hyeok

AU - Kim, Jin Ju

AU - Sim, Woo Sup

AU - Mishchenko, Natalia P.

AU - Fedoreyev, Sergey A.

AU - Vasileva, Elena A.

AU - Ban, Kiwon

AU - Park, Hun Jun

AU - Baek, Sang Hong

N1 - Funding Information: Funding: This work has supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No.2018R1A2B600638013 to S.-H.B. and No.2021R1A4A303187511 to H.-J.P.). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/10

Y1 - 2021/10

N2 - Reactive oxygen species (ROS) and intracellular iron levels are critical modulators of lipid peroxidation that trigger iron-dependent non-apoptotic ferroptosis in myocardial ischemia-reperfusion (I/R) injury. Histochrome (HC), with a potent antioxidant moiety and iron-chelating capacity, is now available in clinical practice. However, limited data are available about the protective effects of HC on ferroptotic cell death in myocardial I/R injury. In this study, we investigated whether the intravenous administration of HC (1 mg/kg) prior to reperfusion could decrease myocardial damage by reducing ferroptosis. Rats undergoing 60 min of ischemia and reperfusion were randomly divided into three groups as follows: (1) Sham, (2) I/R control, and (3) I/R + HC. Serial echocar-diography up to four weeks after I/R injury showed that intravenous injection of HC significantly improved cardiac function compared to the I/R controls. In addition, the hearts of rats who received intravenous injection of HC exhibited significantly lower cardiac fibrosis and higher capillary density. HC treatment decreased intracellular and mitochondrial ROS levels by upregulating the expression of nuclear factor erythroid 2-related factor (Nrf2) and its downstream genes. HC also inhibited erastin-and RSL3-induced ferroptosis in rat neonatal cardiomyocytes by maintaining the intracellular glutathione level and through upregulated activity of glutathione peroxidase 4. These findings suggest that early intervention with HC before reperfusion rescued myocardium from I/R injury by preventing ferroptotic cell death. Therefore, HC is a promising therapeutic option to provide secondary cardioprotection in patients who undergo coronary reperfusion therapy.

AB - Reactive oxygen species (ROS) and intracellular iron levels are critical modulators of lipid peroxidation that trigger iron-dependent non-apoptotic ferroptosis in myocardial ischemia-reperfusion (I/R) injury. Histochrome (HC), with a potent antioxidant moiety and iron-chelating capacity, is now available in clinical practice. However, limited data are available about the protective effects of HC on ferroptotic cell death in myocardial I/R injury. In this study, we investigated whether the intravenous administration of HC (1 mg/kg) prior to reperfusion could decrease myocardial damage by reducing ferroptosis. Rats undergoing 60 min of ischemia and reperfusion were randomly divided into three groups as follows: (1) Sham, (2) I/R control, and (3) I/R + HC. Serial echocar-diography up to four weeks after I/R injury showed that intravenous injection of HC significantly improved cardiac function compared to the I/R controls. In addition, the hearts of rats who received intravenous injection of HC exhibited significantly lower cardiac fibrosis and higher capillary density. HC treatment decreased intracellular and mitochondrial ROS levels by upregulating the expression of nuclear factor erythroid 2-related factor (Nrf2) and its downstream genes. HC also inhibited erastin-and RSL3-induced ferroptosis in rat neonatal cardiomyocytes by maintaining the intracellular glutathione level and through upregulated activity of glutathione peroxidase 4. These findings suggest that early intervention with HC before reperfusion rescued myocardium from I/R injury by preventing ferroptotic cell death. Therefore, HC is a promising therapeutic option to provide secondary cardioprotection in patients who undergo coronary reperfusion therapy.

KW - Anti-ferroptosis

KW - Cardioprotection

KW - Histochrome

KW - Iron-chelating

KW - Ischemia-reperfusion injury

UR - http://www.scopus.com/inward/record.url?scp=85117133009&partnerID=8YFLogxK

U2 - 10.3390/antiox10101624

DO - 10.3390/antiox10101624

M3 - Article

AN - SCOPUS:85117133009

SN - 2076-3921

VL - 10

JO - Antioxidants

JF - Antioxidants

IS - 10

M1 - 1624

ER -

Histochrome attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis-induced cardiomyocyte death

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this