Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusion
Abstract We have previously demonstrated that inhibition of extracellularly oriented carbonic anhydrase (CA) isoforms protects the myocardium against ischemia‐reperfusion injury. In this study, our aim was to assess the possible further contribution of CA intracellular isoforms examining the actions...
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| Format: | Article |
| Language: | English |
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Wiley
2021-11-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.15093 |
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| author | Alejandro Ciocci Pardo Luisa F. González Arbeláez Juliana C. Fantinelli Bernardo V. Álvarez Susana M. Mosca Erik R. Swenson |
| author_facet | Alejandro Ciocci Pardo Luisa F. González Arbeláez Juliana C. Fantinelli Bernardo V. Álvarez Susana M. Mosca Erik R. Swenson |
| author_sort | Alejandro Ciocci Pardo |
| collection | DOAJ |
| description | Abstract We have previously demonstrated that inhibition of extracellularly oriented carbonic anhydrase (CA) isoforms protects the myocardium against ischemia‐reperfusion injury. In this study, our aim was to assess the possible further contribution of CA intracellular isoforms examining the actions of the highly diffusible cell membrane permeant inhibitor of CA, ethoxzolamide (ETZ). Isolated rat hearts, after 20 min of stabilization, were assigned to the following groups: (1) Nonischemic control: 90 min of perfusion; (2) Ischemic control: 30 min of global ischemia and 60 min of reperfusion (R); and (3) ETZ: ETZ at a concentration of 100 μM was administered for 10 min before the onset of ischemia and then during the first 10 min of reperfusion. In additional groups, ETZ was administered in the presence of SB202190 (SB, a p38MAPK inhibitor) or chelerythrine (Chel, a protein kinase C [PKC] inhibitor). Infarct size, myocardial function, and the expression of phosphorylated forms of p38MAPK, PKCε, HSP27, and Drp1, and calcineurin Aβ content were assessed. In isolated mitochondria, the Ca2+ response, Ca2+ retention capacity, and membrane potential were measured. ETZ decreased infarct size by 60%, improved postischemic recovery of myocardial contractile and diastolic relaxation increased P‐p38MAPK, P‐PKCε, P‐HSP27, and P‐Drp1 expression, decreased calcineurin content, and normalized calcium and membrane potential parameters measured in isolated mitochondria. These effects were significantly attenuated when ETZ was administered in the presence of SB or Chel. These data show that ETZ protects the myocardium and mitochondria against ischemia‐reperfusion injury through p38MAPK‐ and PKCε‐dependent pathways and reinforces the role of CA as a possible target in the management of acute cardiac ischemic diseases. |
| first_indexed | 2024-12-19T17:44:15Z |
| format | Article |
| id | doaj.art-7d2166fa400c440bad93b484c3d0272a |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-12-19T17:44:15Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-7d2166fa400c440bad93b484c3d0272a2022-12-21T20:12:07ZengWileyPhysiological Reports2051-817X2021-11-01922n/an/a10.14814/phy2.15093Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusionAlejandro Ciocci Pardo0Luisa F. González Arbeláez1Juliana C. Fantinelli2Bernardo V. Álvarez3Susana M. Mosca4Erik R. Swenson5Centro de Investigaciones Cardiovasculares ¨Dr Horacio E Cingolani¨ CCT‐CONICET Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Buenos Aires ArgentinaCentro de Investigaciones Cardiovasculares ¨Dr Horacio E Cingolani¨ CCT‐CONICET Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Buenos Aires ArgentinaCentro de Investigaciones Cardiovasculares ¨Dr Horacio E Cingolani¨ CCT‐CONICET Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Buenos Aires ArgentinaCentro de Investigaciones Cardiovasculares ¨Dr Horacio E Cingolani¨ CCT‐CONICET Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Buenos Aires ArgentinaCentro de Investigaciones Cardiovasculares ¨Dr Horacio E Cingolani¨ CCT‐CONICET Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Buenos Aires ArgentinaDepartment of Medicine, Pulmonary and Critical Care Medicine VA Puget Sound Health Care SystemUniversity of Washington Seattle Washington USAAbstract We have previously demonstrated that inhibition of extracellularly oriented carbonic anhydrase (CA) isoforms protects the myocardium against ischemia‐reperfusion injury. In this study, our aim was to assess the possible further contribution of CA intracellular isoforms examining the actions of the highly diffusible cell membrane permeant inhibitor of CA, ethoxzolamide (ETZ). Isolated rat hearts, after 20 min of stabilization, were assigned to the following groups: (1) Nonischemic control: 90 min of perfusion; (2) Ischemic control: 30 min of global ischemia and 60 min of reperfusion (R); and (3) ETZ: ETZ at a concentration of 100 μM was administered for 10 min before the onset of ischemia and then during the first 10 min of reperfusion. In additional groups, ETZ was administered in the presence of SB202190 (SB, a p38MAPK inhibitor) or chelerythrine (Chel, a protein kinase C [PKC] inhibitor). Infarct size, myocardial function, and the expression of phosphorylated forms of p38MAPK, PKCε, HSP27, and Drp1, and calcineurin Aβ content were assessed. In isolated mitochondria, the Ca2+ response, Ca2+ retention capacity, and membrane potential were measured. ETZ decreased infarct size by 60%, improved postischemic recovery of myocardial contractile and diastolic relaxation increased P‐p38MAPK, P‐PKCε, P‐HSP27, and P‐Drp1 expression, decreased calcineurin content, and normalized calcium and membrane potential parameters measured in isolated mitochondria. These effects were significantly attenuated when ETZ was administered in the presence of SB or Chel. These data show that ETZ protects the myocardium and mitochondria against ischemia‐reperfusion injury through p38MAPK‐ and PKCε‐dependent pathways and reinforces the role of CA as a possible target in the management of acute cardiac ischemic diseases.https://doi.org/10.14814/phy2.15093carbonic anhydraseethoxzolamideischemia‐reperfusionmitochondriamyocardiump38MAPK |
| spellingShingle | Alejandro Ciocci Pardo Luisa F. González Arbeláez Juliana C. Fantinelli Bernardo V. Álvarez Susana M. Mosca Erik R. Swenson Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusion Physiological Reports carbonic anhydrase ethoxzolamide ischemia‐reperfusion mitochondria myocardium p38MAPK |
| title | Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusion |
| title_full | Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusion |
| title_fullStr | Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusion |
| title_full_unstemmed | Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusion |
| title_short | Myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia‐reperfusion |
| title_sort | myocardial and mitochondrial effects of the anhydrase carbonic inhibitor ethoxzolamide in ischemia reperfusion |
| topic | carbonic anhydrase ethoxzolamide ischemia‐reperfusion mitochondria myocardium p38MAPK |
| url | https://doi.org/10.14814/phy2.15093 |
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