Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury

A mechanism involving calcium overload/XO/ROS/mPTP pathway

Pingjun Zhu, Shunying Hu, Qinhua Jin, Dandan Li, Feng Tian, Sam Q Toan, Yang Li, Hao Zhou, Yundai Chen

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Receptor-interacting protein 3 (Ripk3)-mediated necroptosis contributes to cardiac ischaemia-reperfusion (IR) injury through poorly defined mechanisms. Our results demonstrated that Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H2O2. The higher level of Ripk3 was positively correlated to the infarction area expansion, cardiac dysfunction and augmented cardiomyocytes necroptosis. Function study further illustrated that upregulated Ripk3 evoked the endoplasmic reticulum (ER) stress, which was accompanied with an increase in intracellular Ca2+ level ([Ca2+]c) and xanthine oxidase (XO) expression. Activated XO raised cellular reactive oxygen species (ROS) that mediated the mitochondrial permeability transition pore (mPTP) opening and cardiomyocytes necroptosis. By comparison, genetic ablation of Ripk3 abrogated the ER stress and thus blocked the [Ca2+]c overload-XO-ROS-mPTP pathways, favouring a pro-survival state that ultimately resulted in the inhibition of cardiomyocytes necroptosis in the setting of cardiac IR injury. In summary, the present study helps to elucidate how necroptosis is mediated by ER stress, via the calcium overload /XO/ROS/mPTP opening axis.

Original languageEnglish (US)
Pages (from-to)157-168
Number of pages12
JournalRedox Biology
Volume16
DOIs
StatePublished - Jun 1 2018

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Endoplasmic Reticulum Stress
Xanthine Oxidase
Reperfusion Injury
Cardiac Myocytes
Reactive Oxygen Species
Calcium
Receptor-Interacting Protein Serine-Threonine Kinases
Ablation
Infarction
mitochondrial permeability transition pore

Keywords

  • ER stress
  • Necroptosis
  • ROS
  • Ripk3
  • XO
  • mPTP

Cite this

Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury : A mechanism involving calcium overload/XO/ROS/mPTP pathway. / Zhu, Pingjun; Hu, Shunying; Jin, Qinhua; Li, Dandan; Tian, Feng; Toan, Sam Q; Li, Yang; Zhou, Hao; Chen, Yundai.

In: Redox Biology, Vol. 16, 01.06.2018, p. 157-168.

Research output: Contribution to journalArticle

Zhu, Pingjun ; Hu, Shunying ; Jin, Qinhua ; Li, Dandan ; Tian, Feng ; Toan, Sam Q ; Li, Yang ; Zhou, Hao ; Chen, Yundai. / Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury : A mechanism involving calcium overload/XO/ROS/mPTP pathway. In: Redox Biology. 2018 ; Vol. 16. pp. 157-168.
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