Myocardial fibrosis is a common pathological companion of various cardiovascular diseases. To date, the role of enhancer of zeste homolog 2 (EZH2) in cancer has been well demonstrated including in renal carcinoma and its inhibitors have entered the stage of phase I/II clinical trials. However, the precise mechanism of EZH2 in cardiac diseases is largely unclear. In the current study, we first found that EZH2 expression was increased in Ang-II-treated cardiac fibroblasts (CFs) and mouse heart homogenates following isoproterenol (ISO) administration for 21 days, respectively. Ang-II induces CFs activation and increased collagen-I, collagen-III, α-SMA, EZH2, and trimethylates lysine 27 on histone 3 (H3K27me3) expressions can be reversed by EZH2 inhibitor (GSK126) and EZH2 siRNA. The ISO-induced cardiac hypertrophy, and fibrosis in vivo which were also related to the upregulation of EZH2 and its downstream target, H3K27me3, could be recovered by GSK126. Furthermore, the upregulation of EZH2 induces the decrease of paired box 6 (PAX6) and C-X-C motif ligand 10 (CXCL10) "which" were also reversed by GSK126 treatment. In summary, the present evidence strongly suggests that GSK126 could be a therapeutic intervention, blunting the development and progression of myocardial fibrosis in an EZH2-PAX6-CXCL10-dependent manner.

中文翻译：

---

GSK126 是一种表观遗传调节因子 EZH2 的抑制剂，通过调节 EZH2-PAX6-CXCL10 通路抑制心脏纤维化。

心肌纤维化是各种心血管疾病的共同病理伴侣。目前，zeste homolog 2 (EZH2)增强子在包括肾癌在内的癌症中的作用已得到充分证实，其抑制剂已进入I/II期临床试验阶段。然而，EZH2 在心脏病中的确切机制在很大程度上尚不清楚。在当前的研究中，我们首先发现在异丙肾上腺素 (ISO) 给药 21 天后，Ang-II 处理的心脏成纤维细胞 (CF) 和小鼠心脏匀浆中的 EZH2 表达分别增加。Ang-II 诱导 CFs 激活和增加的胶原蛋白-I、胶原蛋白-III、α-SMA、EZH2 和组蛋白 3 (H3K27me3) 表达上的三甲基化赖氨酸 27 可以被 EZH2 抑制剂 (GSK126) 和 EZH2 siRNA 逆转。ISO诱导的心肌肥大，和体内纤维化也与 EZH2 及其下游靶标 H3K27me3 的上调有关，可以通过 GSK126 恢复。此外，EZH2 的上调诱导配对盒 6 (PAX6) 和 CXC 基序配体 10 (CXCL10) 的减少，“这些”也被 GSK126 处理逆转。总之，目前的证据强烈表明 GSK126 可能是一种治疗干预措施，以 EZH2-PAX6-CXCL10 依赖性方式减缓心肌纤维化的发展和进展。