4-Hydroxy-2-Nonenal Promotes Cardiomyocyte Necroptosis via Stabilizing Receptor-Interacting Serine/Threonine-Protein Kinase 1

Xiaoxuan Zhai; Wenjun Wang; Shukun Sun; Yu Han; Jiaxin Li; Shengchuan Cao; Ruochuan Li; Tonghui Xu; Qiuhuan Yuan; Jiali Wang; Shujian Wei; Yuguo Chen

doi:10.3389/fcell.2021.721795

4-Hydroxy-2-Nonenal Promotes Cardiomyocyte Necroptosis via Stabilizing Receptor-Interacting Serine/Threonine-Protein Kinase 1

Front Cell Dev Biol. 2021 Oct 1:9:721795. doi: 10.3389/fcell.2021.721795. eCollection 2021.

Authors

Xiaoxuan Zhai^{1

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6}, Wenjun Wang^{1

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7}, Shukun Sun^{1

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3

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6}, Yu Han^{1

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6}, Jiaxin Li^{1

2

3

4

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6}, Shengchuan Cao^{1

2

3

4

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6}, Ruochuan Li^{1

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3

4

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6}, Tonghui Xu^{1

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4

5

6}, Qiuhuan Yuan^{1

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3

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6}, Jiali Wang^{1

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3

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6}, Shujian Wei^{1

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3

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6}, Yuguo Chen^{1

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6}

Affiliations

¹ Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Clinical Research Center for Emergency and Critical Care Medicine, Qilu Hospital, Institute of Emergency and Critical Care Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.
³ Key Laboratory of Emergency and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁴ Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁵ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁶ The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁷ Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.

Abstract

Background: Necroptosis is a vital regulator of myocardial ischemia/reperfusion (MI/R) injury. Meanwhile, 4-hydroxy-2-nonenal (4-HNE) is abundantly increased during MI/R injury. However, whether 4-HNE induces cardiomyocyte necroptosis during MI/R remains unknown. Methods: To observe the relationship between 4-HNE and necroptosis during MI/R, C57BL/6 mice and aldehyde dehydrogenase 2-transgenic (ALDH2-Tg) mice were both exposed to left anterior descending artery ligation surgery to establish MI/R injury models. For further study, isolated mouse hearts and H9c2 cells were both treated with 4-HNE to elucidate the underlying mechanisms. Results: Necroptosis and 4-HNE were both upregulated in I/R-injured hearts. Cardiomyocyte necroptosis was significantly decreased in I/R-injured hearts from ALDH2-Tg mice as compared with that of wild-type mice. In vitro studies showed that necroptosis was enhanced by 4-HNE perfusion in a time- and concentration-dependent manner. Knockdown of receptor-interacting serine/threonine-protein kinase 1 (RIP1) using small interfering RNA (siRNA) prevented 4-HNE-induced cardiomyocyte necroptosis, manifesting that RIP1 played a key role in the upregulation of cell necroptosis by 4-HNE. Further studies found that 4-HNE reduced the protein degradation of RIP1 by preventing K48-polyubiquitination of RIP1. Conclusion: 4-HNE contributes to cardiomyocyte necroptosis by regulating ubiquitin-mediated proteasome degradation of RIP1.

Keywords: 4-hydroxynonenal (4-HNE); RIP1 (RIPK1); myocardial ischemia – reperfusion injury (MIRI); necroptosis; ubiquitination.