Shi Zhan-Li, Fang Kun, Li Zhi-Hui, Ren Dan-Hong, Zhang Jia-Ying, Sun Jing
Department of Intensive Care Unit, Hangzhou Red Cross Hospital/Zhejiang Chinese Medicine, Western Medicine Integrated Hospital, Hangzhou 310003, China.
Can Respir J. 2018 Feb 28;2018:9174926. doi: 10.1155/2018/9174926. eCollection 2018.
EPZ005687 is a selective inhibiter of methyltransferase EZH2. In this article, we investigated the protective role and mechanism of EPZ005687 in transverse aortic constriction-induced pulmonary arterial hypertension in mice.
We assigned 15 (6-8 weeks old) male balb/c mice to 3 groups randomly: Sham control + DMSO group, TAC + DMSO group, and TAC + EPZ005687 group (10 mg kg, once a week for 4 weeks). On day 28 following TAC operation, the right ventricular systolic blood pressure (RVSBP) was measured, and lung tissues were collected for laboratory examinations (DHE, Western blot, real-time PCR, and ChIP).
Murine PAH model was successfully created by TAC operation as evidenced by increased RVSBP and hypertrophic right ventricle. Compared with the sham control, TAC-induced PAH markedly upregulated the expression of EZH2 and ROS deposition in lungs in PAH mice. The inhibiter of methyltransferase EZH2, EPZ005687 significantly inhibits the development of TAC-induced PAH in an EZH2-SOD1-ROS dependent manner.
Our data identified that EZH2 serves a fundamental role in TAC-induced PAH, and administration of EPZ005687 might represent a novel therapeutic target for the treatment of TAC-induced PAH.
EPZ005687是甲基转移酶EZH2的选择性抑制剂。在本文中，我们研究了EPZ005687在小鼠横断主动脉缩窄诱导的肺动脉高压中的保护作用及机制。
我们将15只（6 - 8周龄）雄性Balb/c小鼠随机分为3组：假手术对照组 + 二甲基亚砜组、横断主动脉缩窄组 + 二甲基亚砜组和横断主动脉缩窄组 + EPZ005687组（10 mg/kg，每周一次，共4周）。在横断主动脉缩窄手术第28天，测量右心室收缩压（RVSBP），并收集肺组织进行实验室检查（二氢乙锭染色、蛋白质免疫印迹法、实时荧光定量PCR和染色质免疫沉淀法）。
横断主动脉缩窄手术成功建立了小鼠肺动脉高压模型，表现为右心室收缩压升高和右心室肥厚。与假手术对照组相比，横断主动脉缩窄诱导的肺动脉高压显著上调了肺动脉高压小鼠肺组织中EZH2的表达和活性氧沉积。甲基转移酶EZH2的抑制剂EPZ005687以EZH2 - SOD1 - 活性氧依赖的方式显著抑制横断主动脉缩窄诱导的肺动脉高压的发展。
我们的数据表明EZH2在横断主动脉缩窄诱导的肺动脉高压中起重要作用，给予EPZ005687可能是治疗横断主动脉缩窄诱导的肺动脉高压的新治疗靶点。
