Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury

Qingmei Hu¹, Junxia Zhang^{2

3

4}, Xile Luo⁵, Peiyu Hu⁶, Jiayi Li¹, Fan Li¹, Zeyuan Wang⁷, Shuyang Zhang⁷, Zishan Jiao⁸, Yitong Liu⁹, Jiaxin Duanmu⁵, Li Jin¹, Peng Xie¹, Wenneng Zhu^{9

10}, Wen Zheng¹, Haibao Shang¹, Xinli Hu¹, Zhixing Chen^{1

9}, Rui-Ping Xiao^{1

9

11

12}, Yan Zhang^{3

13

14}

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.), Peking University, China.
² Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling (J.Z.), Peking University, China.
³ Beijing Key Laboratory of Cardiovascular Receptors Research, China (J.Z., Y.Z.).
⁴ Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing, China (J.Z.), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁵ Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling (X.L., J.D., Y.Z.), Peking University, China.
⁶ Institute of Energy (P.H.), Peking University, China.
⁷ Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (Z.W., S.Z.), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁸ Institute of Basic Medical Sciences & School of Basic Medicine (Z.J.), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁹ Peking-Tsinghua Center for Life Sciences (Y.L., W. Zhu, Z.C., R.-P.X.), Peking University, China.
¹⁰ Department of Chemical Biology, College of Chemistry (W. Zhu), Peking University, China.
¹¹ Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology (R.-P.X.), Peking University, China.
¹² PKU-Nanjing Joint Institute of Translational Medicine, China (R.-P.X.).
¹³ National Health Council Key Laboratory of Cell Transplantation, First Affiliated Hospital of Harbin Medical University, China (Y.Z.).
¹⁴ Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (Y.Z.).

PMID: 40396239
DOI: 10.1161/CIRCULATIONAHA.124.070936

Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury

Qingmei Hu et al. Circulation. 2025.

. 2025 Jul 8;152(1):41-57.

doi: 10.1161/CIRCULATIONAHA.124.070936. Epub 2025 May 21.

Authors

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology (Q.H., J.L., F.L., L.J., P.X., W. Zheng, H.S., X.H., Z.C., R.-P.X.), Peking University, China.
² Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling (J.Z.), Peking University, China.
³ Beijing Key Laboratory of Cardiovascular Receptors Research, China (J.Z., Y.Z.).
⁴ Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Haihe Laboratory of Cell Ecosystem, Beijing, China (J.Z.), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁵ Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling (X.L., J.D., Y.Z.), Peking University, China.
⁶ Institute of Energy (P.H.), Peking University, China.
⁷ Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (Z.W., S.Z.), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁸ Institute of Basic Medical Sciences & School of Basic Medicine (Z.J.), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁹ Peking-Tsinghua Center for Life Sciences (Y.L., W. Zhu, Z.C., R.-P.X.), Peking University, China.
¹⁰ Department of Chemical Biology, College of Chemistry (W. Zhu), Peking University, China.
¹¹ Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology (R.-P.X.), Peking University, China.
¹² PKU-Nanjing Joint Institute of Translational Medicine, China (R.-P.X.).
¹³ National Health Council Key Laboratory of Cell Transplantation, First Affiliated Hospital of Harbin Medical University, China (Y.Z.).
¹⁴ Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (Y.Z.).

PMID: 40396239
DOI: 10.1161/CIRCULATIONAHA.124.070936

Abstract

Background: Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury.

Methods: The profiling of AA metabolic enzymes was analyzed with the RNA sequencing transcriptome data from the mouse heart tissues with I/R injury. Cultured neonatal and adult rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse I/R models were used to confirm the role of L-PGDS (lipocalin-type prostaglandin D2 synthase)/15d-PGJ2 in I/R injury. A biotin-tagged 15d-PGJ2 analog combined with liquid chromatography-tandem mass spectrometry was used to identify the downstream signaling of L-PGDS/15d-PGJ2.

Results: Based on the transcriptome data and experimental validations, L-PGDS, together with its downstream metabolite 15d-PGJ2, was downregulated in cardiac tissue with I/R injury. Functionally, L-PGDS overexpression mitigates myocardial I/R injury, whereas knockdown exacerbates the damage. Supplementation of 15d-PGJ2 alleviated I/R injury. Mechanistically, 15d-PGJ2 covalently bound to the CaMKII (Ca²⁺/calmodulin dependent protein kinase II) and induced lipoxidation of its cysteine 495 (CaMKII-δ9) to dampen the formation of CaMKII oligomers and alleviate its overactivation, consequently ameliorating cardiomyocyte death and cardiac injury.

Conclusions: Our study uncovered L-PGDS/15d-PGJ2/CaMKII signaling as a new mechanism underlying I/R-induced cardiomyocyte death. This provides new mechanistic insights and therapeutic targets for myocardial I/R injury and subsequent heart failure. We also showed that lipoxidation is a new post-translational modification type for CaMKII, deepening our understanding of the regulation of its activity.

Keywords: 15d-PGJ2; CaMKII; L-PGDS; arachidonic acid; cardioprotection; ischemia/reperfusion injury.

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Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury

Affiliations

Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury

Authors

Affiliations

Abstract

Conflict of interest statement

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Substances

LinkOut - more resources

Full Text Sources

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