Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury
Myocardial ischemia-reperfusion injury increases myocardial microvascular permeability, leading to enhanced microvascular filtration and interstitial fluid accumulation that is associated with greater microvascular obstruction and inadequate myocardial perfusion. A burst of reactive oxygen species a...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Current Issues in Molecular Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1467-3045/47/1/33 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588781062979584 |
|---|---|
| author | Dmitry L. Sonin Mikhail S. Medved Asker Y. Khapchaev Maria V. Sidorova Marina E. Palkeeva Olga A. Kazakova Garry V. Papayan Daniil A. Mochalov Sarkis M. Minasyan Ilya E. Anufriev Daria V. Mukhametdinova Natalia M. Paramonova Ksenia M. Balabanova Anastasia S. Lopatina Ilia V. Aleksandrov Natalya Yu. Semenova Anna A. Kordyukova Kirill V. Zaichenko Vladimir P. Shirinsky Michael M. Galagudza |
| author_facet | Dmitry L. Sonin Mikhail S. Medved Asker Y. Khapchaev Maria V. Sidorova Marina E. Palkeeva Olga A. Kazakova Garry V. Papayan Daniil A. Mochalov Sarkis M. Minasyan Ilya E. Anufriev Daria V. Mukhametdinova Natalia M. Paramonova Ksenia M. Balabanova Anastasia S. Lopatina Ilia V. Aleksandrov Natalya Yu. Semenova Anna A. Kordyukova Kirill V. Zaichenko Vladimir P. Shirinsky Michael M. Galagudza |
| author_sort | Dmitry L. Sonin |
| collection | DOAJ |
| description | Myocardial ischemia-reperfusion injury increases myocardial microvascular permeability, leading to enhanced microvascular filtration and interstitial fluid accumulation that is associated with greater microvascular obstruction and inadequate myocardial perfusion. A burst of reactive oxygen species and inflammatory mediators during reperfusion causes myosin light chain kinase (MLCK)-dependent endothelial hyperpermeability, which is considered a preventable cause of reperfusion injury. In the present study, a single intravenous injection of MLCK peptide inhibitor PIK7 (2.5 mg/kg or 40 mg/kg) was found to suppress the vascular hyperpermeability caused by ischemia/reperfusion injury in an in vivo rat model. The antiedemic effect of PIK7 is transient and ceases within 90 min of reperfusion. The early no-reflow detected for the first time after 30 min ischemia in this model of myocardial infarction reduces the area accessible for PIK7. Electron microscopy has shown membrane-bound blebs of endotheliocytes, which partially or completely obturate the capillary lumen, and few capillaries with signs of intercellular gap formation in samples obtained from the center of the early no-reflow zone in control and PIK7-injected rats. Co-injection of PIK7 with NO donor sodium nitroprusside (SNP) increases blood flow in the zone of early no-reflow, while reducing the increased vascular permeability caused by SNP. |
| format | Article |
| id | doaj-art-863122cc80aa41eb810514e22419366d |
| institution | Kabale University |
| issn | 1467-3037 1467-3045 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj-art-863122cc80aa41eb810514e22419366d2025-01-24T13:27:28ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452025-01-014713310.3390/cimb47010033Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion InjuryDmitry L. Sonin0Mikhail S. Medved1Asker Y. Khapchaev2Maria V. Sidorova3Marina E. Palkeeva4Olga A. Kazakova5Garry V. Papayan6Daniil A. Mochalov7Sarkis M. Minasyan8Ilya E. Anufriev9Daria V. Mukhametdinova10Natalia M. Paramonova11Ksenia M. Balabanova12Anastasia S. Lopatina13Ilia V. Aleksandrov14Natalya Yu. Semenova15Anna A. Kordyukova16Kirill V. Zaichenko17Vladimir P. Shirinsky18Michael M. Galagudza19Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaInstitute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaInstitute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaInstitute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaLaboratory of Radio- and Optoelectronic Devices for Early Diagnostics of Living Systems Pathologies, The Institute for Analytical Instrumentation, Russian Academy of Sciences, 31-33A Ivana Chernykh Street, 198095 Saint Petersburg, RussiaLaboratory of Radio- and Optoelectronic Devices for Early Diagnostics of Living Systems Pathologies, The Institute for Analytical Instrumentation, Russian Academy of Sciences, 31-33A Ivana Chernykh Street, 198095 Saint Petersburg, RussiaInstitute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, RussiaInstitute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, RussiaMyocardial ischemia-reperfusion injury increases myocardial microvascular permeability, leading to enhanced microvascular filtration and interstitial fluid accumulation that is associated with greater microvascular obstruction and inadequate myocardial perfusion. A burst of reactive oxygen species and inflammatory mediators during reperfusion causes myosin light chain kinase (MLCK)-dependent endothelial hyperpermeability, which is considered a preventable cause of reperfusion injury. In the present study, a single intravenous injection of MLCK peptide inhibitor PIK7 (2.5 mg/kg or 40 mg/kg) was found to suppress the vascular hyperpermeability caused by ischemia/reperfusion injury in an in vivo rat model. The antiedemic effect of PIK7 is transient and ceases within 90 min of reperfusion. The early no-reflow detected for the first time after 30 min ischemia in this model of myocardial infarction reduces the area accessible for PIK7. Electron microscopy has shown membrane-bound blebs of endotheliocytes, which partially or completely obturate the capillary lumen, and few capillaries with signs of intercellular gap formation in samples obtained from the center of the early no-reflow zone in control and PIK7-injected rats. Co-injection of PIK7 with NO donor sodium nitroprusside (SNP) increases blood flow in the zone of early no-reflow, while reducing the increased vascular permeability caused by SNP.https://www.mdpi.com/1467-3045/47/1/33myosin light chain kinasepeptide inhibitor PIK7ischemic and reperfusion injurymyocardial infarctionno-reflowmicrovascular hyperpermeability |
| spellingShingle | Dmitry L. Sonin Mikhail S. Medved Asker Y. Khapchaev Maria V. Sidorova Marina E. Palkeeva Olga A. Kazakova Garry V. Papayan Daniil A. Mochalov Sarkis M. Minasyan Ilya E. Anufriev Daria V. Mukhametdinova Natalia M. Paramonova Ksenia M. Balabanova Anastasia S. Lopatina Ilia V. Aleksandrov Natalya Yu. Semenova Anna A. Kordyukova Kirill V. Zaichenko Vladimir P. Shirinsky Michael M. Galagudza Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury Current Issues in Molecular Biology myosin light chain kinase peptide inhibitor PIK7 ischemic and reperfusion injury myocardial infarction no-reflow microvascular hyperpermeability |
| title | Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury |
| title_full | Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury |
| title_fullStr | Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury |
| title_full_unstemmed | Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury |
| title_short | Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury |
| title_sort | antiedemic effect of the myosin light chain kinase inhibitor pik7 in the rat model of myocardial ischemia reperfusion injury |
| topic | myosin light chain kinase peptide inhibitor PIK7 ischemic and reperfusion injury myocardial infarction no-reflow microvascular hyperpermeability |
| url | https://www.mdpi.com/1467-3045/47/1/33 |
| work_keys_str_mv | AT dmitrylsonin antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT mikhailsmedved antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT askerykhapchaev antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT mariavsidorova antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT marinaepalkeeva antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT olgaakazakova antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT garryvpapayan antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT daniilamochalov antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT sarkismminasyan antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT ilyaeanufriev antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT dariavmukhametdinova antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT nataliamparamonova antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT kseniambalabanova antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT anastasiaslopatina antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT iliavaleksandrov antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT natalyayusemenova antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT annaakordyukova antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT kirillvzaichenko antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT vladimirpshirinsky antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury AT michaelmgalagudza antiedemiceffectofthemyosinlightchainkinaseinhibitorpik7intheratmodelofmyocardialischemiareperfusioninjury |