2. Academic Validation
  3. EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2

EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2

  • Redox Biol. 2023 Sep:65:102825. doi: 10.1016/j.redox.2023.102825.
Bei Wang 1,  Yuxuan Jin 2,  Jiao Liu 1,  Qian Liu 1,  Yujun Shen 1,  Shengkai Zuo 3,  Ying Yu 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 2 Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 3 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Biopharmaceutics, School of Pharmacy, Tianjin Medical University, Tianjin, China. Electronic address: [email protected].
  • 4 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address: [email protected].
PMID: 37531930 DOI: 10.1016/j.redox.2023.102825
Abstract

Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in Cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE2 production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a Ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte Ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the Ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced Ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as Glutathione Peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with Gαq to elicit intracellular CA2+ flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced Ferroptosis in human cardiomyocytes. Thus, PGE2/EP1 axis protects cardiomyocytes from DOX-induced Ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.

Keywords

Cardiomyocyte ferroptosis; DOX-induced cardiomyopathy; EP1; Nrf2.

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