Plasminogen activator inhibitor-1 (PAI-1) has a cardioprotective function in mice by repressing cardiac fibrosis through TGF-β and plasminogen-mediated pathways. In addition it is known to be involved in the recruitment and polarization of monocytes/macrophages towards a M2 phenotype in cancer. Here, we investigated the expression of PAI-1 in human dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi) and its effect on cardiac fibrosis and macrophage polarization. We retrospectively analyzed endomyocardial biopsies (EMBs) of patients with DCM or DCMi for PAI-1 expression by immunohistochemistry. Furthermore, EMBs were evaluated for the content of fibrotic tissue, number of activated myofibroblasts, TGF-β expression, as well as for M1 and M2 macrophages. Patients with high-grade DCMi (DCMi-high, CD3⁺ lymphocytes > 30 cells/mm²) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3⁺ lymphocytes = 14–30 cells/mm²) (15.5 ± 0.4% vs. 1.0 ± 0.1% and 4.0 ± 0.1%, p ≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of cardiac fibrosis, decreased levels of TGF-β and reduced number of myofibroblasts. In addition, DCMi-high patients revealed an increased proportion of non-classical M2 macrophages towards classical M1 macrophages, indicating M2 macrophage-favoring properties of PAI-1 in inflammatory cardiomyopathies. Our findings give evidence that elevated expression of cardiac PAI-1 in subjects with high-grade DCMi suppresses fibrosis by inhibiting TGF-β and myofibroblast activation. Moreover, our data indicate that PAI-1 is involved in the polarization of M2 macrophages in the heart. Thus, PAI-1 could serve as a potential prognostic biomarker and as a possible therapeutic target in inflammatory cardiomyopathies.

纤溶酶原激活物抑制剂-1 (PAI-1) 通过 TGF-β 和纤溶酶原介导的途径抑制心脏纤维化，在小鼠中具有心脏保护功能。此外，已知它参与单核细胞/巨噬细胞向癌症中的 M2 表型的募集和极化。在这里，我们研究了 PAI-1 在人类扩张型心肌病 (DCM) 和炎症性扩张型心肌病 (DCMi) 中的表达及其对心脏纤维化和巨噬细胞极化的影响。我们通过免疫组织化学回顾性分析了 DCM 或 DCMi 患者的心内膜心肌活检 (EMB) 中的 PAI-1 表达。此外，还评估了 EMB 的纤维化组织含量、活化的肌成纤维细胞数量、TGF-β 表达以及 M1 和 M2 巨噬细胞。高级别 DCMi (DCMi-high, CD3 ⁺淋巴细胞 > 30 个细胞/mm ²）与 DCM 和低级别 DCMi 患者（DCMi-low，CD3 ⁺淋巴细胞 = 14–30 个细胞/mm ²）相比，PAI-1 水平显着增加（15.5 ± 0.4% vs. 1.0 ± 0.1% 和 4.0 ± 0.1%，p ≤ 0.001)。DCMi 高受试者中 PAI-1 表达升高与心脏纤维化程度降低、TGF-β 水平降低和肌成纤维细胞数量减少有关。此外，DCMi 高的患者显示非经典 M2 巨噬细胞对经典 M1 巨噬细胞的比例增加，表明 PAI-1 在炎性心肌病中的 M2 巨噬细胞偏好特性。我们的研究结果证明，高级别 DCMi 受试者心脏 PAI-1 的表达升高通过抑制 TGF-β 和肌成纤维细胞活化来抑制纤维化。此外，我们的数据表明 PAI-1 参与了心脏中 M2 巨噬细胞的极化。因此，PAI-1 可以作为潜在的预后生物标志物和炎症性心肌病的可能治疗靶点。