Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice
The size of the infarct area following acute myocardial infarction (AMI) is a critical prognostic factor. Caspase-11-dependent pyroptosis has been implicated as a key mechanism driving cardiomyocyte death after AMI. However, no therapeutic agents have been developed to inhibit myocardial cell death...
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Elsevier
2025-06-01
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| Series: | Journal of Molecular and Cellular Cardiology Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S277297612500011X |
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| author | Tetsuro Marunouchi Mayu Kyono Naoko Kikuchi Kouichi Tanonaka |
| author_facet | Tetsuro Marunouchi Mayu Kyono Naoko Kikuchi Kouichi Tanonaka |
| author_sort | Tetsuro Marunouchi |
| collection | DOAJ |
| description | The size of the infarct area following acute myocardial infarction (AMI) is a critical prognostic factor. Caspase-11-dependent pyroptosis has been implicated as a key mechanism driving cardiomyocyte death after AMI. However, no therapeutic agents have been developed to inhibit myocardial cell death by targeting caspase-11. This study investigates the effects of gemfibrozil, a potential caspase-11 inhibitor, on ischemia/reperfusion-induced myocardial pyroptosis in mice. To model AMI, the left coronary artery of C57BL/6 N mice was ligated for 1 h, followed by reperfusion. Levels of cleaved caspase-11 and the N-terminal fragment of gasdermin D (GSDMD-N) in ischemic myocardial tissue increased progressively over time after ischemia/reperfusion. Gemfibrozil treatment during reperfusion significantly attenuated these increases in cleaved caspase-11 and GSDMD-N levels. Moreover, gemfibrozil reduced the extent of myocardial infarct size during reperfusion. In cultured cardiomyocytes isolated from adult mice, hypoxia/reoxygenation-induced increases in caspase-11 and GSDMD cleavage were similarly mitigated by gemfibrozil, which concurrently prevented necrotic cell death. These findings demonstrate the involvement of caspase-11-dependent pyroptosis in myocardial cell death following ischemia/reperfusion and suggest that gemfibrozil holds promise as a therapeutic agent for reducing myocardial infarct size after AMI. |
| format | Article |
| id | doaj-art-86dfbcfe52894c2b93c76f19724fbfdb |
| institution | DOAJ |
| issn | 2772-9761 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Molecular and Cellular Cardiology Plus |
| spelling | doaj-art-86dfbcfe52894c2b93c76f19724fbfdb2025-08-20T02:39:37ZengElsevierJournal of Molecular and Cellular Cardiology Plus2772-97612025-06-011210029210.1016/j.jmccpl.2025.100292Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in miceTetsuro Marunouchi0Mayu Kyono1Naoko Kikuchi2Kouichi Tanonaka3Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, JapanDepartment of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, JapanDepartment of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, JapanCorresponding author at: Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.; Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, JapanThe size of the infarct area following acute myocardial infarction (AMI) is a critical prognostic factor. Caspase-11-dependent pyroptosis has been implicated as a key mechanism driving cardiomyocyte death after AMI. However, no therapeutic agents have been developed to inhibit myocardial cell death by targeting caspase-11. This study investigates the effects of gemfibrozil, a potential caspase-11 inhibitor, on ischemia/reperfusion-induced myocardial pyroptosis in mice. To model AMI, the left coronary artery of C57BL/6 N mice was ligated for 1 h, followed by reperfusion. Levels of cleaved caspase-11 and the N-terminal fragment of gasdermin D (GSDMD-N) in ischemic myocardial tissue increased progressively over time after ischemia/reperfusion. Gemfibrozil treatment during reperfusion significantly attenuated these increases in cleaved caspase-11 and GSDMD-N levels. Moreover, gemfibrozil reduced the extent of myocardial infarct size during reperfusion. In cultured cardiomyocytes isolated from adult mice, hypoxia/reoxygenation-induced increases in caspase-11 and GSDMD cleavage were similarly mitigated by gemfibrozil, which concurrently prevented necrotic cell death. These findings demonstrate the involvement of caspase-11-dependent pyroptosis in myocardial cell death following ischemia/reperfusion and suggest that gemfibrozil holds promise as a therapeutic agent for reducing myocardial infarct size after AMI.http://www.sciencedirect.com/science/article/pii/S277297612500011XCaspase-11PyroptosisGemfibrozilIschemiaReperfusion |
| spellingShingle | Tetsuro Marunouchi Mayu Kyono Naoko Kikuchi Kouichi Tanonaka Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice Journal of Molecular and Cellular Cardiology Plus Caspase-11 Pyroptosis Gemfibrozil Ischemia Reperfusion |
| title | Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice |
| title_full | Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice |
| title_fullStr | Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice |
| title_full_unstemmed | Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice |
| title_short | Gemfibrozil mitigates caspase-11-driven myocardial pyroptosis in ischemia/reperfusion injury in mice |
| title_sort | gemfibrozil mitigates caspase 11 driven myocardial pyroptosis in ischemia reperfusion injury in mice |
| topic | Caspase-11 Pyroptosis Gemfibrozil Ischemia Reperfusion |
| url | http://www.sciencedirect.com/science/article/pii/S277297612500011X |
| work_keys_str_mv | AT tetsuromarunouchi gemfibrozilmitigatescaspase11drivenmyocardialpyroptosisinischemiareperfusioninjuryinmice AT mayukyono gemfibrozilmitigatescaspase11drivenmyocardialpyroptosisinischemiareperfusioninjuryinmice AT naokokikuchi gemfibrozilmitigatescaspase11drivenmyocardialpyroptosisinischemiareperfusioninjuryinmice AT kouichitanonaka gemfibrozilmitigatescaspase11drivenmyocardialpyroptosisinischemiareperfusioninjuryinmice |