Aziz Shireen, Yalan Li, Raza Muhammad Ahmer, Lemin Jiao, Akram Hafiz Muhamamd Bilal, Zhao Wen
State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Biochem Cell Biol. 2023 Feb 1;101(1):87-100. doi: 10.1139/bcb-2022-0224. Epub 2022 Dec 5.
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.
心肌纤维化是各种心血管疾病常见的病理伴随症状。迄今为止，zeste同源物2增强子（EZH2）在癌症中的作用已得到充分证实，包括在肾癌中，其抑制剂已进入I/II期临床试验阶段。然而，EZH2在心脏疾病中的精确机制在很大程度上尚不清楚。在本研究中，我们首先发现，在分别用血管紧张素II（Ang-II）处理心脏成纤维细胞（CFs）以及用异丙肾上腺素（ISO）给药21天的小鼠心脏匀浆中，EZH2表达均增加。Ang-II诱导CFs活化，并且I型胶原、III型胶原、α-平滑肌肌动蛋白（α-SMA）、EZH2以及组蛋白3赖氨酸27三甲基化（H3K27me3）的表达增加，而这些可被EZH2抑制剂（GSK126）和EZH2小干扰RNA（siRNA）逆转。ISO诱导的体内心脏肥大和纤维化也与EZH2及其下游靶点H3K27me3的上调有关，而GSK126可使其恢复。此外，EZH2的上调诱导配对盒6（PAX6）和C-X-C基序配体10（CXCL10）减少，而GSK126处理也可使其逆转。总之，目前的证据强烈表明，GSK126可能是一种治疗干预手段，以EZH2-PAX6-CXCL10依赖的方式抑制心肌纤维化的发生和发展。
