Iron Overload via Heme Degradation in the Endoplasmic Reticulum Triggers Ferroptosis in Myocardial Ischemia-Reperfusion Injury

Hiroko Deguchi Miyamoto; Masataka Ikeda; Tomomi Ide; Tomonori Tadokoro; Shun Furusawa; Ko Abe; Kosei Ishimaru; Nobuyuki Enzan; Masashi Sada; Taishi Yamamoto; Shouji Matsushima; Tomoko Koumura; Ken-Ichi Yamada; Hirotaka Imai; Hiroyuki Tsutsui

doi:10.1016/j.jacbts.2022.03.012

Iron Overload via Heme Degradation in the Endoplasmic Reticulum Triggers Ferroptosis in Myocardial Ischemia-Reperfusion Injury

JACC Basic Transl Sci. 2022 Jul 27;7(8):800-819. doi: 10.1016/j.jacbts.2022.03.012. eCollection 2022 Aug.

Authors

Hiroko Deguchi Miyamoto^{1

2}, Masataka Ikeda^{1

2}, Tomomi Ide^{1

2}, Tomonori Tadokoro^{1

2}, Shun Furusawa^{1

2}, Ko Abe^{1

2}, Kosei Ishimaru^{1

2}, Nobuyuki Enzan^{1

2}, Masashi Sada^{1

2}, Taishi Yamamoto^{1

2}, Shouji Matsushima^{1

2}, Tomoko Koumura³, Ken-Ichi Yamada⁴, Hirotaka Imai³, Hiroyuki Tsutsui^{1

2}

Affiliations

¹ Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Hygienic Chemistry and Medical Research Laboratories, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
⁴ Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Abstract

Ischemia-reperfusion (I/R) injury is a promising therapeutic target to improve clinical outcomes after acute myocardial infarction. Ferroptosis, triggered by iron overload and excessive lipid peroxides, is reportedly involved in I/R injury. However, its significance and mechanistic basis remain unclear. Here, we show that glutathione peroxidase 4 (GPx4), a key endogenous suppressor of ferroptosis, determines the susceptibility to myocardial I/R injury. Importantly, ferroptosis is a major mode of cell death in I/R injury, distinct from mitochondrial permeability transition (MPT)-driven necrosis. This suggests that the use of therapeutics targeting both modes is an effective strategy to further reduce the infarct size and thereby ameliorate cardiac remodeling after I/R injury. Furthermore, we demonstrate that heme oxygenase 1 up-regulation in response to hypoxia and hypoxia/reoxygenation degrades heme and thereby induces iron overload and ferroptosis in the endoplasmic reticulum (ER) of cardiomyocytes. Collectively, ferroptosis triggered by GPx4 reduction and iron overload in the ER is distinct from MPT-driven necrosis in both in vivo phenotype and in vitro mechanism for I/R injury. The use of therapeutics targeting ferroptosis in conjunction with cyclosporine A can be a promising strategy for I/R injury.

Keywords: AMI, acute myocardial infarction; CsA, cyclosporine A; CypD, cyclophilin D; DXZ, dexrazoxane; ER, endoplasmic reticulum; Fer-1, ferrostatin-1; GPx4, glutathione peroxidase 4; H/R, hypoxia-reoxygenation; HF, heart failure; HO-1, heme oxygenase 1; I/R, ischemia-reperfusion; LP, lipid peroxide; MPT, mitochondrial permeability transition; MPT-driven necrosis; RCD, regulated cell death; STEMI, ST-segment elevation myocardial infarction; cyclosporine A; ferroptosis; glutathione peroxidase 4; ischemia-reperfusion injury.