October 30, 2023
Keio University School of Medicine
Center for Cancer Immunotherapy and Immunobiology, Kyoto University
A joint research team—comprising Assistant Professor Genki Ichihara (at the time of the research) and Associate Professor Motoaki Sano of the Division of Cardiology, Department of Internal Medicine, Keio University School of Medicine; Senior Lecturer Yoshinori Katsumata of the university's Institute for Integrated Sports Medicine; and Program-Specific Associate Professor Yuki Sugiura of the Kyoto University Graduate School of Medicine—has discovered a new therapeutic approach focusing on the "metabolic changes" in myocardial infarction. Myocardial infarction is a disease in which blood flow to the heart muscle is blocked, and currently, myocardial damage tends to progress even after treatment. As the disease progresses extremely rapidly, research has primarily been conducted "after" the pathological condition has advanced. In this study, the research team used live disease model mice to observe in detail the process by which myocardial ischemia-reperfusion injury progresses in stages, using a new "monitoring method with metabolic molecules." By utilizing this new method, they identified the mechanism by which the function of eliminating harmful reactive oxygen species, caused by myocardial infarction, gradually declines. Furthermore, by applying this finding and intervening in the metabolic pathway that enhances the removal of reactive oxygen species, they confirmed that it is possible to reduce myocardial damage after ischemia-reperfusion injury.
Myocardial infarction (ischemic heart disease) is a leading cause of death, and it is known that even with treatment (reperfusion therapy), there is a high risk of myocardial necrosis and heart failure. In particular, the generation of reactive oxygen species immediately after reperfusion has been considered a problem, but the development of effective treatments has proven difficult. This study focused on the "oxidation of lipids by reactive oxygen species" in the cell membrane. It is also known that when cell membrane lipids are excessively oxidized, the membrane can no longer maintain its structure, leading to the death of the entire cell. This form of cell death is called ferroptosis. The study elucidated that in cardiac ischemia-reperfusion injury, the accumulation of oxidized lipids and ferroptosis begins at a relatively late stage (6 hours or more after reperfusion). The cause was identified as the leakage of a powerful reducing substance, glutathione, out of the cell via a specific transporter (mainly MRP1: multidrug resistance protein 1) during ischemia-reperfusion. In this study, a detailed analysis of myocardial ischemia-reperfusion injury was conducted using state-of-the-art metabolic analysis technology. As a result, we were able to identify a new therapeutic target that can control the increase of reactive oxygen species and oxidized lipids within myocardial cells and suppress the progression of the cell death process known as ferroptosis. This new therapeutic approach is expected to become an important option for saving the lives of patients with myocardial infarction, improving their quality of life, and supporting their recovery from the disease.
These research findings were published in the journal Circulation Research on October 11, 2023 (US time).
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