Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury
Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia‐reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparti...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-06-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.019521 |
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| author | Gentaro Ikeda Tetsuya Matoba Ayako Ishikita Kazuhiro Nagaoka Kaku Nakano Jun‐ichiro Koga Hiroyuki Tsutsui Kensuke Egashira |
| author_facet | Gentaro Ikeda Tetsuya Matoba Ayako Ishikita Kazuhiro Nagaoka Kaku Nakano Jun‐ichiro Koga Hiroyuki Tsutsui Kensuke Egashira |
| author_sort | Gentaro Ikeda |
| collection | DOAJ |
| description | Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia‐reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle‐mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C‐C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30–45 minutes) after reperfusion, whereas C‐C chemokine receptor 2 contributes to IR injury at later time point (45–60 minutes) after reperfusion. Double deficiency of CypD and C‐C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C‐C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly‐6Chigh monocytes after myocardial IR injury. In CypD‐knockout mice, administration of interleukin‐1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly‐lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte‐mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle‐mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury. |
| first_indexed | 2024-12-18T10:49:02Z |
| format | Article |
| id | doaj.art-da210d10d67e4303b06574fa0d6e1404 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-18T10:49:02Z |
| publishDate | 2021-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-da210d10d67e4303b06574fa0d6e14042022-12-21T21:10:30ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802021-06-01101210.1161/JAHA.120.019521Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion InjuryGentaro Ikeda0Tetsuya Matoba1Ayako Ishikita2Kazuhiro Nagaoka3Kaku Nakano4Jun‐ichiro Koga5Hiroyuki Tsutsui6Kensuke Egashira7Department of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka JapanDepartment of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka JapanDepartment of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka JapanDepartment of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka JapanDepartment of Cardiovascular Research Development, and Translational Medicine Center for Disruptive Cardiovascular Innovation Kyushu University Fukuoka JapanDepartment of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka JapanDepartment of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka JapanDepartment of Cardiovascular Research Development, and Translational Medicine Center for Disruptive Cardiovascular Innovation Kyushu University Fukuoka JapanBackground The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia‐reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle‐mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C‐C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30–45 minutes) after reperfusion, whereas C‐C chemokine receptor 2 contributes to IR injury at later time point (45–60 minutes) after reperfusion. Double deficiency of CypD and C‐C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C‐C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly‐6Chigh monocytes after myocardial IR injury. In CypD‐knockout mice, administration of interleukin‐1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly‐lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte‐mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle‐mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.https://www.ahajournals.org/doi/10.1161/JAHA.120.019521cardioprotectiondrug delivery systemischemia‐reperfusion injurynanotechnology |
| spellingShingle | Gentaro Ikeda Tetsuya Matoba Ayako Ishikita Kazuhiro Nagaoka Kaku Nakano Jun‐ichiro Koga Hiroyuki Tsutsui Kensuke Egashira Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cardioprotection drug delivery system ischemia‐reperfusion injury nanotechnology |
| title | Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury |
| title_full | Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury |
| title_fullStr | Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury |
| title_full_unstemmed | Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury |
| title_short | Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury |
| title_sort | nanoparticle mediated simultaneous targeting of mitochondrial injury and inflammation attenuates myocardial ischemia reperfusion injury |
| topic | cardioprotection drug delivery system ischemia‐reperfusion injury nanotechnology |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.019521 |
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