Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids

Calvin Yeang, Devin Hasanally, Xuchu Que, Ming Yow Hung, Aleksandra Stamenkovic, David Chan, Rakesh Chaudhary, Victoria Margulets, Andrea L. Edel, Masahiko Hoshijima, Yusu Gu, William Bradford, Nancy Dalton, Phuong Miu, David Yc Cheung, Davinder S. Jassal, Grant N. Pierce, Kirk L. Peterson, Lorrie A. Kirshenbaum, Joseph L. WitztumSotirios Tsimikas, Amir Ravandi

研究成果: 雜誌貢獻文章

10 引文 (Scopus)

摘要

Aims: Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results: OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P < 0.05 to P < 0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6 ± 4.14% and with PONPC was 25.3 ± 3.4% compared to 8.0 ± 1.6% and 6.4 ± 1.0%, respectively, with the addition of E06, P < 0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4 ± 21.9% vs. 47.7 ± 17.6%, P = 0.023). Conclusions: OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.
原文英語
頁(從 - 到)179-189
頁數11
期刊Cardiovascular Research
115
發行號1
DOIs
出版狀態已發佈 - 一月 1 2019

指紋

Myocardial Reperfusion Injury
Reperfusion Injury
Phosphatidylcholines
Cardiac Myocytes
Myocardial Ischemia
Phospholipids
Cell Death
Myocardial Infarction
Cell Fractionation
Single-Chain Antibodies
Respiratory Burst
Spectrophotometry
Transgenic Mice
Reperfusion
Cell Survival
Mitochondria
Oxidative Stress
Monoclonal Antibodies
Lipids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

引用此文

Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids. / Yeang, Calvin; Hasanally, Devin; Que, Xuchu; Hung, Ming Yow; Stamenkovic, Aleksandra; Chan, David; Chaudhary, Rakesh; Margulets, Victoria; Edel, Andrea L.; Hoshijima, Masahiko; Gu, Yusu; Bradford, William; Dalton, Nancy; Miu, Phuong; Cheung, David Yc; Jassal, Davinder S.; Pierce, Grant N.; Peterson, Kirk L.; Kirshenbaum, Lorrie A.; Witztum, Joseph L.; Tsimikas, Sotirios; Ravandi, Amir.

於: Cardiovascular Research, 卷 115, 編號 1, 01.01.2019, p. 179-189.

研究成果: 雜誌貢獻文章

Yeang, C, Hasanally, D, Que, X, Hung, MY, Stamenkovic, A, Chan, D, Chaudhary, R, Margulets, V, Edel, AL, Hoshijima, M, Gu, Y, Bradford, W, Dalton, N, Miu, P, Cheung, DY, Jassal, DS, Pierce, GN, Peterson, KL, Kirshenbaum, LA, Witztum, JL, Tsimikas, S & Ravandi, A 2019, 'Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids', Cardiovascular Research, 卷 115, 編號 1, 頁 179-189. https://doi.org/10.1093/cvr/cvy136
Yeang, Calvin ; Hasanally, Devin ; Que, Xuchu ; Hung, Ming Yow ; Stamenkovic, Aleksandra ; Chan, David ; Chaudhary, Rakesh ; Margulets, Victoria ; Edel, Andrea L. ; Hoshijima, Masahiko ; Gu, Yusu ; Bradford, William ; Dalton, Nancy ; Miu, Phuong ; Cheung, David Yc ; Jassal, Davinder S. ; Pierce, Grant N. ; Peterson, Kirk L. ; Kirshenbaum, Lorrie A. ; Witztum, Joseph L. ; Tsimikas, Sotirios ; Ravandi, Amir. / Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids. 於: Cardiovascular Research. 2019 ; 卷 115, 編號 1. 頁 179-189.
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title = "Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids",
abstract = "Aims: Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results: OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P < 0.05 to P < 0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6 ± 4.14{\%} and with PONPC was 25.3 ± 3.4{\%} compared to 8.0 ± 1.6{\%} and 6.4 ± 1.0{\%}, respectively, with the addition of E06, P < 0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4 ± 21.9{\%} vs. 47.7 ± 17.6{\%}, P = 0.023). Conclusions: OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.",
author = "Calvin Yeang and Devin Hasanally and Xuchu Que and Hung, {Ming Yow} and Aleksandra Stamenkovic and David Chan and Rakesh Chaudhary and Victoria Margulets and Edel, {Andrea L.} and Masahiko Hoshijima and Yusu Gu and William Bradford and Nancy Dalton and Phuong Miu and Cheung, {David Yc} and Jassal, {Davinder S.} and Pierce, {Grant N.} and Peterson, {Kirk L.} and Kirshenbaum, {Lorrie A.} and Witztum, {Joseph L.} and Sotirios Tsimikas and Amir Ravandi",
year = "2019",
month = "1",
day = "1",
doi = "10.1093/cvr/cvy136",
language = "English",
volume = "115",
pages = "179--189",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids

AU - Yeang, Calvin

AU - Hasanally, Devin

AU - Que, Xuchu

AU - Hung, Ming Yow

AU - Stamenkovic, Aleksandra

AU - Chan, David

AU - Chaudhary, Rakesh

AU - Margulets, Victoria

AU - Edel, Andrea L.

AU - Hoshijima, Masahiko

AU - Gu, Yusu

AU - Bradford, William

AU - Dalton, Nancy

AU - Miu, Phuong

AU - Cheung, David Yc

AU - Jassal, Davinder S.

AU - Pierce, Grant N.

AU - Peterson, Kirk L.

AU - Kirshenbaum, Lorrie A.

AU - Witztum, Joseph L.

AU - Tsimikas, Sotirios

AU - Ravandi, Amir

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Aims: Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results: OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P < 0.05 to P < 0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6 ± 4.14% and with PONPC was 25.3 ± 3.4% compared to 8.0 ± 1.6% and 6.4 ± 1.0%, respectively, with the addition of E06, P < 0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4 ± 21.9% vs. 47.7 ± 17.6%, P = 0.023). Conclusions: OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.

AB - Aims: Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results: OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P < 0.05 to P < 0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6 ± 4.14% and with PONPC was 25.3 ± 3.4% compared to 8.0 ± 1.6% and 6.4 ± 1.0%, respectively, with the addition of E06, P < 0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4 ± 21.9% vs. 47.7 ± 17.6%, P = 0.023). Conclusions: OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.

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U2 - 10.1093/cvr/cvy136

DO - 10.1093/cvr/cvy136

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JF - Cardiovascular Research

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