GSK126 an inhibitor of epigenetic regulator EZH2 suppresses cardiac fibrosis by regulating the EZH2-PAX6-CXCL10 pathway
GSK126 an inhibitor of epigenetic regulator EZH2 suppresses cardiac fibrosis by regulating the EZH2-PAX6-CXCL10 pathway
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GSK126 是表观遗传调节因子 EZH2 的抑制剂，通过调节 EZH2-PAX6-CXCL10 通路抑制心脏纤维化
DOI：
10.1139/bcb-2022-0224
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发表时间：
2023-01-09
影响因子：
2.9
通讯作者：
Zhao, Wen
中科院分区：
文献类型：
--
作者：
Aziz, Shireen;Yalan, Li;Zhao, Wen
心肌纤维化是多种心血管疾病共同的病理伴发。到目前为止，ZAST同源基因增强子2(EZH2)在包括肾癌在内的肿瘤中的作用已经得到了很好的证明，其抑制剂已经进入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还不清楚。在目前的研究中，我们首次发现在给予异丙肾上腺素(ISO)21天后，经Ang-II处理的心脏成纤维细胞(CFs)和小鼠心脏匀浆中EZH2的表达分别增加。Ang-II诱导CFs活化，I型胶原、III型胶原、α-SMA、EZH2及其三甲基赖氨酸27在组蛋白3(H3K27me3)上的表达增加可被EZH2抑制剂(GSK126)和EZH2 siRNA逆转。与EZH2及其下游靶基因H3K27me3表达上调有关的在体心肌肥大和纤维化也可被GSK126逆转。此外，EZH2上调导致配对框6(PAX6)和C-X-C基序配体10(CXCL10)“减少”，这也被GSK126逆转。综上所述，目前的证据有力地表明GSK126可能是一种治疗干预，以EZH2-PAX6-CXCL10依赖的方式钝化心肌纤维化的发生和进展。
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, alpha-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.