{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:31:51Z","timestamp":1791361911402,"version":"4.3.1"},"reference-count":59,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Acute myocardial infarction (AMI) remains one of the leading causes of mortality worldwide. Recently, a cardioprotective effect of clusterin (CLU), a ubiquitous extracellular chaperone, has been reported. However, the underlying mechanisms remain unresolved. We hypothesized that CLU exerts its protective effect on AMI by neutralizing cytotoxic and proinflammatory properties of extracellular histones, a new class of damage\u2010associated molecular patterns (DAMPs), that are released after massive cell injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>In vitro, we showed that exogenous CLU reduces histone\u2010induced cell death in H9C2 cells after hypoxia\u2212reoxygenation (.78\u2009\u00b1\u2009.15 vs. 1.39\u2009\u00b1\u2009.20; <jats:italic>p<\/jats:italic>\u2009=\u2009.0059). Moreover, we found increased CLU protein levels in the ischemic zone vs. non\u2010ischemic zone after AMI in mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05). Correspondingly, CLU\u2010deficient (CLU<jats:sup>\u2212\/\u2212<\/jats:sup>) mice presented significantly increased infarct size vs. wild\u2010type (CLU<jats:sup>+\/+<\/jats:sup>) mice (46.29\u2009\u00b1\u20095.13% vs. 27.47\u2009\u00b1\u20091.92%; <jats:italic>p<\/jats:italic>\u2009=\u2009.0176). This cardioprotective effect of CLU is accompanied by an attenuation of the post\u2010AMI proinflammatory response through a decrease in the expression of proinflammatory cytokines interleukin (IL)\u20106 and IL\u20101\u03b2, a decrease in phosphorylated nuclear factor kappa B (NF\u2010kB) p65, as well as a decrease in the activation of the nucleotide\u2010binding oligomerization domain (NOD)\u2010like receptor pyrin domain containing 3 (NLRP3) inflammasome. Also, we found that in patients with acute ST\u2010segment elevation myocardial infarction (STEMI), circulating CLU\u2010histone complexes were significantly increased compared to healthy controls (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>From these results, CLU protects the heart from inflammatory injury in AMI and this cardioprotection is due at least in part to its ability to neutralise extracellular histones released from the damaged tissue.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.70076","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T07:49:19Z","timestamp":1748245759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cardioprotective effects of the extracellular chaperone clusterin in acute myocardial 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