Allawa Louwana, Poirier Antoine, Pignon Pascale, Beaumont Justine, Lebeau Lucie, Barbelivien Agnès, Bochaton Thomas, Beauvillain Céline, Henrion Daniel, Delneste Yves, Jeannin Pascale, Prunier Fabrice, Tamareille Sophie
CNRS, Inserm, Laboratoire MITOVASC, SFR ICAT, Univ Angers, Angers, France.
Service de Cardiologie, CHU Angers, Angers, France.
Eur J Clin Invest. 2025 Oct;55(10):e70076. doi: 10.1111/eci.70076. Epub 2025 May 26.
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-associated molecular patterns (DAMPs), that are released after massive cell injury.
In vitro, we showed that exogenous CLU reduces histone-induced cell death in H9C2 cells after hypoxia-reoxygenation (.78 ± .15 vs. 1.39 ± .20; p = .0059). Moreover, we found increased CLU protein levels in the ischemic zone vs. non-ischemic zone after AMI in mice (p < .05). Correspondingly, CLU-deficient (CLU) mice presented significantly increased infarct size vs. wild-type (CLU) mice (46.29 ± 5.13% vs. 27.47 ± 1.92%; p = .0176). This cardioprotective effect of CLU is accompanied by an attenuation of the post-AMI proinflammatory response through a decrease in the expression of proinflammatory cytokines interleukin (IL)-6 and IL-1β, a decrease in phosphorylated nuclear factor kappa B (NF-kB) p65, as well as a decrease in the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Also, we found that in patients with acute ST-segment elevation myocardial infarction (STEMI), circulating CLU-histone complexes were significantly increased compared to healthy controls (p < .001).
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.
急性心肌梗死（AMI）仍是全球主要的死亡原因之一。最近，有报道称一种普遍存在的细胞外伴侣蛋白簇集素（CLU）具有心脏保护作用。然而，其潜在机制仍未明确。我们推测，CLU通过中和细胞外组蛋白的细胞毒性和促炎特性来对AMI发挥保护作用，细胞外组蛋白是一类新的损伤相关分子模式（DAMPs），在大量细胞损伤后释放。
在体外实验中，我们发现外源性CLU可降低缺氧复氧后H9C2细胞中组蛋白诱导的细胞死亡（0.78±0.15对1.39±0.20；p = 0.0059）。此外，我们发现小鼠AMI后缺血区的CLU蛋白水平高于非缺血区（p < 0.05）。相应地，与野生型（CLU）小鼠相比，CLU基因缺陷（CLU）小鼠的梗死面积显著增加（46.29±5.13%对27.47±1.92%；p = 0.0176）。CLU的这种心脏保护作用伴随着AMI后促炎反应的减弱，这是通过促炎细胞因子白细胞介素（IL）-6和IL-1β表达的降低、磷酸化核因子κB（NF-κB）p65的减少以及含核苷酸结合寡聚化结构域（NOD）样受体吡咯结构域3（NLRP3）炎性小体的激活减少来实现的。此外，我们发现急性ST段抬高型心肌梗死（STEMI）患者循环中的CLU-组蛋白复合物与健康对照相比显著增加（p < 0.001）。
从这些结果来看，CLU可保护心脏免受AMI中的炎症损伤，且这种心脏保护作用至少部分归因于其中和受损组织释放的细胞外组蛋白的能力。
