Suppression of lncRNA <i>Gm47283</i> attenuates myocardial infarction via <i>miR-706</i>/ <i>Ptgs2</i>/ferroptosis axis

Myocardial infarction (MI) is the leading cause of sudden death. Long non-doing RNAs (lncRNAs) were demonstrated to play crucial roles in multiple diseases, including cancer and cardiovascular diseases. Nevertheless, the molecular mechanism of lncNRAs in MI is unclear. In this study, we integrated bioinformatics and molecular biological experiments to identify the novel lncRNA transcripts and elucidated its regulatory mechanism in MI. First, we identified 10 dysregualted lncRNAs and found that lncRNA <i>Gm47283</i> was the top risk factor in MI. Bioinformatics analysis predicted that lncRNA <i>Gm47283</i> exerted function via targeting <i>miR-706</i> and <i>Ptgs2. Ptgs2</i> was also the known regulator of ferroptosis. Inhibition or overexpression of lncRNA <i>Gm47283</i> could regulate <i>Ptgs2</i> expression and downstream ferroptosis activity. Overexpression of <i>miR-706</i> could inhibit the expression of <i>Ptgs2</i> and the activity of ferroptosis, thereby attenuated cellular injury. Mechanically, co-transfection experiments showed that overexpression of <i>miR-706</i> could reverse the damage effect that was caused by lncRNA <i>Gm47283</i> overexpression, via inhibiting <i>Ptgs2</i> and ferroptosis. Additionally, inhibition of lncRNA <i>Gm47283</i> by stem cell membrane coated siRNA could attenuate MI in <i>vivo</i>. Our study elucidated a novel mechanism containing lncRNA <i>Gm47283</i>/<i>miR-706</i>/<i>Ptgs2</i>/ferroptosis in MI, which provided a potential therapeutic for MI. Graphical Abstract. Stem cell membrane coated siRNA of lncRNA <i>Gm47283</i> inhibits cardiomyocyte ferroptosis in myocardial infarction rat. Stem cell membrane-coated siRNA of lncRNA <i>Gm47283</i> increases <i>miR-706</i>, and then <i>miR-706</i> suppresses the <i>expression of Ptgs2</i> to reduce lipid peroxidation toxicity, and then inhibits cardiomyocyte ferroptosis. PUFA: polyunsaturated fatty acid.

心肌梗死（Myocardial infarction, MI）是心源性猝死的首要诱因。长链非编码RNA（long non-coding RNAs, lncRNAs）已被证实于包括肿瘤、心血管疾病在内的多种疾病中发挥关键调控作用。然而，lncRNAs在心肌梗死中的分子机制尚未明确。
本研究整合生物信息学与分子生物学实验手段，鉴定新型lncRNA转录本并阐明其在心肌梗死中的调控机制。首先，我们筛选得到10个差异表达的lncRNAs，发现lncRNA Gm47283是心肌梗死中最关键的风险因子。生物信息学分析预测，lncRNA Gm47283通过靶向miR-706与Ptgs2发挥功能；其中Ptgs2亦是已知的铁死亡（ferroptosis）调控因子。
对lncRNA Gm47283进行敲低或过表达，均可调控Ptgs2的表达水平及下游铁死亡活性。过表达miR-706可抑制Ptgs2的表达与铁死亡活性，从而减轻细胞损伤。机制层面，共转染实验证实，过表达miR-706可通过抑制Ptgs2与铁死亡过程，逆转lncRNA Gm47283过表达所引发的细胞损伤效应。
此外，采用干细胞膜包被的siRNA靶向敲低lncRNA Gm47283，可在体内减轻心肌梗死损伤。本研究阐明了一条以lncRNA Gm47283/miR-706/Ptgs2/铁死亡为核心的心肌梗死调控新机制，为心肌梗死的治疗提供了潜在靶点。
图形摘要：干细胞膜包被的lncRNA Gm47283 siRNA可改善心肌梗死大鼠的心肌细胞铁死亡。具体而言，该递送系统可提升miR-706水平，进而通过抑制Ptgs2的表达以降低脂质过氧化毒性，最终抑制心肌细胞铁死亡。PUFA：多不饱和脂肪酸（polyunsaturated fatty acid）。