MRP1-Dependent Extracellular Release of Glutathione Induces Cardiomyocyte Ferroptosis After Ischemia-Reperfusion

Author:

Ichihara Genki1ORCID,Katsumata Yoshinori12ORCID,Sugiura Yuki34ORCID,Matsuoka Yuta45ORCID,Maeda Rae4,Endo Jin1ORCID,Anzai Atsushi1,Shirakawa Kohsuke1,Moriyama Hidenori1ORCID,Kitakata Hiroki1,Hiraide Takahiro1,Goto Shinichi167ORCID,Ko Seien1ORCID,Iwasawa Yuji1,Sugai Kazuhisa1ORCID,Daigo Kyohei1ORCID,Goto Shinya8ORCID,Sato Kazuki2ORCID,Yamada Ken-ichi5,Suematsu Makoto39,Ieda Masaki1ORCID,Sano Motoaki1ORCID

Affiliation:

1. Department of Cardiology (G.I., Y.K., J.E., A.A., K. Shirakawa, H.M., H.K., T.H., Shinichi Goto, S.K., Y.I., K. Sugai, K.D., M.I., M. Sano), Keio University School of Medicine, Tokyo, Japan.

2. Institute for Integrated Sports Medicine (Y.K., K. Sato), Keio University School of Medicine, Tokyo, Japan.

3. Department of Biochemistry (Y.S., M. Suematsu), Keio University School of Medicine, Tokyo, Japan.

4. Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology (CCII), Kyoto University Graduate School of Medicine, Kyoto, Japan (Y.S., Y.M., R.M.).

5. Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Kyushu, Japan (Y.M., K.Y.).

6. Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan (Shinichi Goto)

7. Division of Cardiovascular Medicine, Brigham and Women’s Hospital, MA, USA (Shinichi Goto)

8. Department of Medicine (Cardiology), Tokai University School of Medicine, Kanagawa, Japan (Shinya Goto).

9. Central Institute for Experimental Medicine and Life Science, Kanagawa, Japan (M. Suematsu).

Abstract

BACKGROUND: The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential for maintaining cellular functions. However, the relationship between disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis. METHODS: In vivo fluctuations of both intra- and extracellular metabolite levels during IR were explored via microdialysis and tissue metabolome analysis. Oxidized phosphatidylcholines were assessed using liquid chromatography high-resolution mass spectrometry. The areas at risk following IR were assessed using triphenyl-tetrazolium chloride/Evans blue stain. RESULTS: Metabolomic analysis combined with microdialysis revealed a significant release of glutathione from the ischemic region into extracellular spaces during ischemia and after reperfusion. The release of glutathione into extracellular spaces and a concomitant decrease in intracellular glutathione concentrations were also observed during anoxia-reperfusion in an in vitro cardiomyocyte model. This extracellular glutathione release was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly MRP1 (multidrug resistance protein 1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple oxidized phosphatidylcholines were significantly elevated in the ischemic region 12 hours after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of oxidized phosphatidylcholines. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury. CONCLUSIONS: Glutathione was released continuously during IR, primarily in an MRP1-dependent manner, and induced ferroptosis. Suppression of glutathione release attenuated ferroptosis and reduced myocardial infarct size following IR.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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