The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion Injury
Myocardial ischemia–reperfusion injury (MI/R) is a negative and adverse cardiovascular outcome following myocardial ischemia, cardiac surgery, or circulatory arrest. Prolyl endopeptidase (PREP) appears to be involved in inflammatory responses, so it could be a possible therapeutic target for counter...
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MDPI AG
2025-04-01
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| Series: | Antioxidants |
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| author | Laura Cucinotta Nicoletta Palermo Alessio Ardizzone Anna Paola Capra Michela Campolo Emanuela Esposito Giovanna Casili Marika Lanza |
| author_facet | Laura Cucinotta Nicoletta Palermo Alessio Ardizzone Anna Paola Capra Michela Campolo Emanuela Esposito Giovanna Casili Marika Lanza |
| author_sort | Laura Cucinotta |
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| description | Myocardial ischemia–reperfusion injury (MI/R) is a negative and adverse cardiovascular outcome following myocardial ischemia, cardiac surgery, or circulatory arrest. Prolyl endopeptidase (PREP) appears to be involved in inflammatory responses, so it could be a possible therapeutic target for counteracting ischemia injury. This study aimed to investigate the role of PREP inhibitor, KYP-2047 (4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrolidine), in the modulation of molecular and biochemical processes involved in MI/R. MI/R was induced through coronary artery occlusion (15 min), followed by reperfusion (2 h). KYP-2047 was intraperitoneally administrated at doses of 2.5 mg/kg and 5 mg/kg 24 h before the surgical procedures. The hearts were removed and processed for analysis. KYP-2047 treatment limited ischemic myocardial-induced histological damage and neutrophil accumulation, limiting inflammation, fibrosis, and apoptosis processes. Additionally, KYP-2047 was able to modulate p-38 and p-ERK expression, suggesting an improving role in recovering cardiac function. These findings highlighted the protective effects of KYP-2047 pretreatment in MI/R injury, suggesting PREP as a potential target therapy for the pathogenesis of MI/R. Although the molecular mechanisms underlying the action of KYP-2047 are still to be explored, these results suggested that the regulation of NF-κB, apoptosis, and MAPK pathways by KYP-2047 treatment could preventatively limit the damage caused by MI/R. |
| format | Article |
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| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Antioxidants |
| spelling | doaj-art-37c4ae55befb459299a7b9c7a30d8ac52025-08-20T02:24:43ZengMDPI AGAntioxidants2076-39212025-04-0114444210.3390/antiox14040442The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion InjuryLaura Cucinotta0Nicoletta Palermo1Alessio Ardizzone2Anna Paola Capra3Michela Campolo4Emanuela Esposito5Giovanna Casili6Marika Lanza7Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria, 1, 98125 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, ItalyMyocardial ischemia–reperfusion injury (MI/R) is a negative and adverse cardiovascular outcome following myocardial ischemia, cardiac surgery, or circulatory arrest. Prolyl endopeptidase (PREP) appears to be involved in inflammatory responses, so it could be a possible therapeutic target for counteracting ischemia injury. This study aimed to investigate the role of PREP inhibitor, KYP-2047 (4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrolidine), in the modulation of molecular and biochemical processes involved in MI/R. MI/R was induced through coronary artery occlusion (15 min), followed by reperfusion (2 h). KYP-2047 was intraperitoneally administrated at doses of 2.5 mg/kg and 5 mg/kg 24 h before the surgical procedures. The hearts were removed and processed for analysis. KYP-2047 treatment limited ischemic myocardial-induced histological damage and neutrophil accumulation, limiting inflammation, fibrosis, and apoptosis processes. Additionally, KYP-2047 was able to modulate p-38 and p-ERK expression, suggesting an improving role in recovering cardiac function. These findings highlighted the protective effects of KYP-2047 pretreatment in MI/R injury, suggesting PREP as a potential target therapy for the pathogenesis of MI/R. Although the molecular mechanisms underlying the action of KYP-2047 are still to be explored, these results suggested that the regulation of NF-κB, apoptosis, and MAPK pathways by KYP-2047 treatment could preventatively limit the damage caused by MI/R.https://www.mdpi.com/2076-3921/14/4/442myocardial ischemia/reperfusion injury (MI/R)prolyl endopeptidaseKYP-2047MAPKNF-κB |
| spellingShingle | Laura Cucinotta Nicoletta Palermo Alessio Ardizzone Anna Paola Capra Michela Campolo Emanuela Esposito Giovanna Casili Marika Lanza The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion Injury Antioxidants myocardial ischemia/reperfusion injury (MI/R) prolyl endopeptidase KYP-2047 MAPK NF-κB |
| title | The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion Injury |
| title_full | The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion Injury |
| title_fullStr | The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion Injury |
| title_full_unstemmed | The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion Injury |
| title_short | The Inhibition of Prolyl Endopeptidase (PREP) by KYP-2047 Treatment to Reduce Myocardial Ischemia/Reperfusion Injury |
| title_sort | inhibition of prolyl endopeptidase prep by kyp 2047 treatment to reduce myocardial ischemia reperfusion injury |
| topic | myocardial ischemia/reperfusion injury (MI/R) prolyl endopeptidase KYP-2047 MAPK NF-κB |
| url | https://www.mdpi.com/2076-3921/14/4/442 |
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