The Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
The Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
Exp Cell Res. 2023 Jun 1;427(1):113572. doi: 10.1016/j.yexcr.2023.113572. Epub 2023 Mar 27.
Long non-coding RNAs (lncRNAs) are pivotal regulators in heart disease, including myocardial ischemia/reperfusion (I/R) injury. LncRNA just proximal to XIST (JPX) is a molecular switch for X-chromosome inactivation. Enhancer of zeste homolog 2 (EZH2) is a core catalytic subunit of the polycomb repressive complex 2 (PRC2), which is involved in chromatin compaction and gene repression. This study aims to explore the mechanism of JPX regulating the expression of Sarcoplasmic/endoplasmic reticulum Ca ATPase 2a (SERCA2a) by binding to EZH2 and preventing cardiomyocyte I/R damage in vivo and in vitro. First, we constructed mouse myocardial I/R and HL1 cell hypoxia/reoxygenation models, and found that JPX was low expressed in both models. JPX overexpression alleviated cardiomyocyte apoptosis in vivo and in vitro, reduced the I/R-induced infarct size in mouse hearts, lowered the serum cTnI concentration, and promoted mouse cardiac systolic function. The evidence implies that JPX can alleviate I/R-induced acute cardiac damage. Mechanistically, the FISH and RIP assays showed that JPX could bind to EZH2. The ChIP assay revealed EZH2 enrichment at the promoter region of SERCA2a. Both the EZH2 and H3K27me3 levels at the promoter region of SERCA2a were reduced in the JPX overexpression group compared to those in the Ad-EGFP group (P < 0.01). In summary, our results suggested that LncRNA JPX directly bound to EZH2 and reduced the EZH2-mediated H3K27me3 in the SERCA2a promoter region, protecting the heart from acute myocardial I/R injury. Therefore, JPX might be a potential therapeutic target for I/R injury.
长链非编码 RNA（lncRNA）是心脏病的关键调节因子，包括心肌缺血/再灌注（I/R）损伤。紧邻 X 染色体失活特异转录物（XIST）的长链非编码 RNA（lncRNA）是 X 染色体失活的分子开关。增强子的外显子 2（EZH2）是多梳抑制复合物 2（PRC2）的核心催化亚基，参与染色质紧缩和基因抑制。本研究旨在探讨 JPX 通过与 EZH2 结合来调节肌浆网/内质网 Ca2+-ATP 酶 2a（SERCA2a）表达的机制，从而防止体内和体外心肌 I/R 损伤。首先，我们构建了小鼠心肌 I/R 和 HL1 细胞缺氧/复氧模型，发现这两种模型中 JPX 的表达均较低。JPX 的过表达减轻了体内和体外心肌细胞的凋亡，减少了小鼠心脏的 I/R 诱导梗死面积，降低了血清 cTnI 浓度，并促进了小鼠心脏的收缩功能。这表明 JPX 可以减轻 I/R 引起的急性心脏损伤。机制上，FISH 和 RIP 检测显示 JPX 可与 EZH2 结合。ChIP 检测显示 EZH2 在 SERCA2a 启动子区域富集。与 Ad-EGFP 组相比，JPX 过表达组中 SERCA2a 启动子区域的 EZH2 和 H3K27me3 水平均降低（P<0.01）。综上所述，我们的研究结果表明，LncRNA JPX 可直接与 EZH2 结合，降低 EZH2 介导的 SERCA2a 启动子区域的 H3K27me3，从而保护心脏免受急性心肌 I/R 损伤。因此，JPX 可能是 I/R 损伤的潜在治疗靶点。
