Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity
To study the relationship between caspase-1/4 and reperfusion injury, we measured infarct size (IS) in isolated mouse hearts undergoing 50 min global ischemia/2 h reperfusion. Starting VRT-043198 (VRT) at reperfusion halved IS. The pan-caspase inhibitor emricasan duplicated VRT’s protection. IS in c...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3801 |
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| author | Xi-Ming Yang Michael V. Cohen Sarah Sayner Jonathon P. Audia James M. Downey |
| author_facet | Xi-Ming Yang Michael V. Cohen Sarah Sayner Jonathon P. Audia James M. Downey |
| author_sort | Xi-Ming Yang |
| collection | DOAJ |
| description | To study the relationship between caspase-1/4 and reperfusion injury, we measured infarct size (IS) in isolated mouse hearts undergoing 50 min global ischemia/2 h reperfusion. Starting VRT-043198 (VRT) at reperfusion halved IS. The pan-caspase inhibitor emricasan duplicated VRT’s protection. IS in caspase-1/4-knockout hearts was similarly reduced, supporting the hypothesis that caspase-1/4 was VRT’s only protective target. NLRC4 inflammasomes activate caspase-1. NLRC4 knockout hearts were not protected, eliminating NLRC4 as caspase-1/4’s activator. The amount of protection that could be achieved by only suppressing caspase-1/4 activity was limited. In wild-type (WT) hearts, ischemic preconditioning (IPC) was as protective as caspase-1/4 inhibitors. Combining IPC and emricasan in these hearts or preconditioning caspase-1/4-knockout hearts produced an additive IS reduction, indicating that more protection could be achieved by combining treatments. We determined when caspase-1/4 exerted its lethal injury. Starting VRT after 10 min of reperfusion in WT hearts was no longer protective, revealing that caspase-1/4 inflicted its injury within the first 10 min of reperfusion. Ca<sup>++</sup> influx at reperfusion might activate caspase-1/4. We tested whether Ca<sup>++</sup>-dependent soluble adenylyl cyclase (AC10) could be responsible. However, IS in AC10<sup>−/−</sup> hearts was not different from that in WT control hearts. Ca<sup>++</sup>-activated calpain has been implicated in reperfusion injury. Calpain could be releasing actin-bound procaspase-1 in cardiomyocytes, which would explain why caspase-1/4-related injury is confined to early reperfusion. The calpain inhibitor calpeptin duplicated emricasan’s protection. Unlike IPC, adding calpain to emricasan offered no additional protection, suggesting that caspase-1/4 and calpain may share the same protective target. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:42:32Z |
| publishDate | 2023-02-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ff634aa12a77442ebfa6396c8e0e2c852023-11-16T21:05:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244380110.3390/ijms24043801Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain ActivityXi-Ming Yang0Michael V. Cohen1Sarah Sayner2Jonathon P. Audia3James M. Downey4Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USADepartment of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USADepartment of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USADepartment of Microbiology, College of Medicine, University of South Alabama, Mobile, AL 36688, USADepartment of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USATo study the relationship between caspase-1/4 and reperfusion injury, we measured infarct size (IS) in isolated mouse hearts undergoing 50 min global ischemia/2 h reperfusion. Starting VRT-043198 (VRT) at reperfusion halved IS. The pan-caspase inhibitor emricasan duplicated VRT’s protection. IS in caspase-1/4-knockout hearts was similarly reduced, supporting the hypothesis that caspase-1/4 was VRT’s only protective target. NLRC4 inflammasomes activate caspase-1. NLRC4 knockout hearts were not protected, eliminating NLRC4 as caspase-1/4’s activator. The amount of protection that could be achieved by only suppressing caspase-1/4 activity was limited. In wild-type (WT) hearts, ischemic preconditioning (IPC) was as protective as caspase-1/4 inhibitors. Combining IPC and emricasan in these hearts or preconditioning caspase-1/4-knockout hearts produced an additive IS reduction, indicating that more protection could be achieved by combining treatments. We determined when caspase-1/4 exerted its lethal injury. Starting VRT after 10 min of reperfusion in WT hearts was no longer protective, revealing that caspase-1/4 inflicted its injury within the first 10 min of reperfusion. Ca<sup>++</sup> influx at reperfusion might activate caspase-1/4. We tested whether Ca<sup>++</sup>-dependent soluble adenylyl cyclase (AC10) could be responsible. However, IS in AC10<sup>−/−</sup> hearts was not different from that in WT control hearts. Ca<sup>++</sup>-activated calpain has been implicated in reperfusion injury. Calpain could be releasing actin-bound procaspase-1 in cardiomyocytes, which would explain why caspase-1/4-related injury is confined to early reperfusion. The calpain inhibitor calpeptin duplicated emricasan’s protection. Unlike IPC, adding calpain to emricasan offered no additional protection, suggesting that caspase-1/4 and calpain may share the same protective target.https://www.mdpi.com/1422-0067/24/4/3801AC10cardioprotectioncalpaincaspase-1emricasanVRT-043198 |
| spellingShingle | Xi-Ming Yang Michael V. Cohen Sarah Sayner Jonathon P. Audia James M. Downey Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity International Journal of Molecular Sciences AC10 cardioprotection calpain caspase-1 emricasan VRT-043198 |
| title | Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity |
| title_full | Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity |
| title_fullStr | Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity |
| title_full_unstemmed | Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity |
| title_short | Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity |
| title_sort | lethal caspase 1 4 dependent injury occurs in the first minutes of coronary reperfusion and requires calpain activity |
| topic | AC10 cardioprotection calpain caspase-1 emricasan VRT-043198 |
| url | https://www.mdpi.com/1422-0067/24/4/3801 |
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