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

Miyamoto, Hiroko Deguchi; Ikeda, Masataka; Ide, Tomomi; Tadokoro, Tomonori; Furusawa, Shun; Ishimaru, Kosei; Enzan, Nobuyuki; Sada, Masafumi; Yamamoto, Taishi; Matsushima, Shouji; Koumura, Tomoko; Yamada, Kazutoyo; Imai, Hideki; Tsutsui, Hiroyuki

doi:10.1016/j.jacbts.2022.03.012

Cited by 58 publications

(59 citation statements)

References 46 publications

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“…Enzymatic activities of complexes I and IV were measured as previously described ( 46 ) using the Complex I Enzyme Activity Assay Kit (ab109721, Abcam) and Complex IV Rodent Enzyme Activity Microplate Assay Kit (ab109911, Abcam) in accordance with the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis

et al. 2022

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Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.

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Section: Methodsmentioning

confidence: 99%

Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis

et al. 2022

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“…The cell survival assay was performed using Cell Counting Kit-F (343-07743, Dojindo, Kumamoto, Japan), as previously described. 28 Briefly, after washing with PBS, cultured cardiomyocytes were incubated in Calcein-AM DMSO solution (diluted 500 times with PBS) at room temperature for 15 min. Then, cell survival was fluorometrically measured (excitation wavelength, 490 nm; emission wavelength, 520 nm) using a Varioskan LUX Multimode Microplate Reader (VLB000D0, Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Ethoxyquin is a competent radical-trapping antioxidant for preventing ferroptosis in doxorubicin cardiotoxicity

Tadokoro

Ikeda

Ide

et al. 2022

Journal of Cardiovascular Pharmacology

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Doxorubicin (DOX) is an effective anti-cancer agent for various malignancies. Nevertheless, it has a side effect of cardiotoxicity, referred to as doxorubicin-induced cardiomyopathy (DIC), that is associated with a poorer prognosis. This cardiotoxicity limits the clinical use of DOX as a therapeutic agent for malignancies. Recently, ferroptosis, a form of regulated cell death induced by the accumulation of lipid peroxides, has been recognized as a major pathophysiology of DIC. Ethoxyquin is a lipophilic antioxidant widely used for food preservation and thus may be a potential therapeutic drug for preventing DIC. However, the efficacy of ethoxyquin against ferroptosis and DIC remains to be fully elucidated. Here, we investigated the inhibitory action of ethoxyquin against GPx4-deficient ferroptosis and its therapeutic efficacy against DOX-induced cell death in cultured cardiomyocytes and cardiotoxicity in a murine model of DIC. In cultured cardiomyocytes, ethoxyquin treatment effectively prevented GPx4-deficient ferroptosis. Ethoxyquin also prevented DOX-induced cell death, accompanied by the suppression of malondialdehyde (MDA) and mitochondrial lipid peroxides, which were induced by DOX. Furthermore, ethoxyquin significantly prevented DOX-induced cell death without any suppression of caspase cleavages representing apoptosis. In DIC mice, ethoxyquin treatment ameliorated cardiac impairments, such as contractile dysfunction and myocardial atrophy, and lung congestion. Ethoxyquin also suppressed serum lactate dehydrogenase and creatine kinase activities, decreased the levels of lipid peroxides such as MDA and acrolein, inhibited cardiac fibrosis, and reduced TUNEL-positive cells in the hearts of DIC mice. Collectively, ethoxyquin is a competent antioxidant for preventing ferroptosis in DIC and can be its prospective therapeutic drug.

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“…The GPX4 levels were reduced in the left anterior descending ligation-induced MI mouse model, and depletion or inhibition of GPX4 led to the overproduction of lipid peroxide and ferroptosis-related H9c2 cell death [ 65 ]. In the myocardial I/R injury mice model, overexpression of GPX4 mitigated ferroptosis and myocardial impairments ( Table 2 ) [ 15 ]. In addition, the upregulation of HMOX1 induced by hypoxia and hypoxia/reoxygenation(H/R) promoted heme degradation and iron accumulation in the endoplasmic reticulum and aggravated ferroptosis in cardiomyocytes [ 15 ].…”

Section: Iron Metabolism Ferroptosis and Cardiovascular Diseasesmentioning

confidence: 99%

“…Currently, cardiovascular diseases (CVDs) are the leading causes of mortality and morbidity worldwide in noncommunicable diseases [ 8 ]. Recently, accumulating evidence confirmed the crucial roles of iron metabolism and ferroptosis in the physiology and pathophysiology of cardiovascular dysfunctions, including atherosclerosis [ 9 , 10 , 11 ], hypertension [ 12 ], pulmonary hypertension (PH) [ 13 ], myocardial ischemia/reperfusion (I/R) injury [ 14 , 15 ], cardiomyopathy [ 16 , 17 ], and heart failure [ 18 ] ( Figure 1 ). In this article, we focus on the impacts and underlying mechanisms of iron metabolism and ferroptosis in the pathogenesis of CVDs and highlight the potential therapeutic value of targeting iron metabolism and ferroptosis in CVDs.…”

Section: Introductionmentioning

confidence: 99%

Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

Chen

Wang

et al. 2023

Nutrients

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Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.

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

Cited by 58 publications

References 46 publications

Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis

Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis

Ethoxyquin is a competent radical-trapping antioxidant for preventing ferroptosis in doxorubicin cardiotoxicity

Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

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