{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T18:15:48Z","timestamp":1772648148670,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL-121513"],"award-info":[{"award-number":["HL-121513"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL-118334"],"award-info":[{"award-number":["HL-118334"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019s protection. IS in caspase-1\/4-knockout hearts was similarly reduced, supporting the hypothesis that caspase-1\/4 was VRT\u2019s only protective target. NLRC4 inflammasomes activate caspase-1. NLRC4 knockout hearts were not protected, eliminating NLRC4 as caspase-1\/4\u2019s 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++ influx at reperfusion might activate caspase-1\/4. We tested whether Ca++-dependent soluble adenylyl cyclase (AC10) could be responsible. However, IS in AC10\u2212\/\u2212 hearts was not different from that in WT control hearts. Ca++-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\u2019s protection. Unlike IPC, adding calpain to emricasan offered no additional protection, suggesting that caspase-1\/4 and calpain may share the same protective target.<\/jats:p>","DOI":"10.3390\/ijms24043801","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T02:31:23Z","timestamp":1676428283000},"page":"3801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Lethal Caspase-1\/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity"],"prefix":"10.3390","volume":"24","author":[{"given":"Xi-Ming","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4543-6708","authenticated-orcid":false,"given":"Michael V.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Department of Medicine, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Sayner","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathon P.","family":"Audia","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James M.","family":"Downey","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s00395-018-0692-z","article-title":"Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function","volume":"113","author":"Audia","year":"2018","journal-title":"Basic Res Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1073\/pnas.041611398","article-title":"Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1\u03b2","volume":"98","author":"Pomerantz","year":"2001","journal-title":"Proc. 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