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《工程(英文)》 >> 2023年 第20卷 第1期 doi: 10.1016/j.eng.2022.08.012

作为一种新的心肌细胞代谢改变和焦亡调节剂,CPAL可调节小鼠心肌梗死损伤

a State-Province Key Laboratories of Biomedicine-Pharmaceutics of China & Key Laboratory of Cardiovascular Medicine Research (Ministry of Education of the People’s Republic of China), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
b Institute of Clinical Pharmacy, The University Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions, Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
c Research Unit of Noninfectious Chronic Diseases in Frigid Zones (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
d Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150081, China

收稿日期: 2022-02-22 修回日期: 2022-07-21 录用日期: 2022-08-04 发布日期: 2022-10-14

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摘要

心肌梗死(myocardial infarction, MI)是一种严重的缺血性心脏病疾病,常伴有心肌代谢紊乱和心肌细胞死亡。越来越多的证据表明,长链非编码RNA(lncRNA)参与癌症及心血管疾病(cardiovascular diseases, CVD)等多种疾病的病理过程,并逐渐成为这些疾病的一种新的生物标志物。本研究旨在探究lncRNA在调节心肌梗死后心肌重构中的作用及机制。研究发现三磷酸腺苷(ATP)在急性心肌梗死边缘区心肌组织中含量减少,糖脂代谢相关基因如分化抗原簇36(CD36)、己糖激酶1(HK1)和葡萄糖转运蛋白4(GLUT4)的表达水平也明显异常,并伴有心肌细胞焦亡的发生。随后发现一种此前未知的保守的lncRNA,即AK009126(心肌细胞焦亡相关lncRNA, CPAL)。实时荧光定量PCR结果显示,CPAL在心肌梗死小鼠的心脏梗死边缘区组织中显著上调。此外,腺相关病毒9(AAV9)通过其短发夹RNA(shRNA)介导的内源性CPAL沉默,可以部分消除缺血小鼠的心肌代谢紊乱,并抑制心肌细胞焦亡。研究结果显示CPAL具有直接结合核因子kappa B(NFκB)的能力,并作为NFκB的激活剂诱导心肌细胞NFκB磷酸化,活化后的NFκB在转录水平促进含半胱氨酸的天冬氨酸蛋白水解酶1(caspase-1)的转录,进而促进其翻译。同时,CPAL增加了心肌细胞中白细胞介素(interleukin, IL)-18 和IL-1β的释放。总的来说,本研究揭示了lncRNA CPAL可能是心肌梗死后诱导心脏代谢异常和心肌细胞焦亡的一种新调节因子,并提示CPAL可能成为治疗心肌细胞缺血损伤的新靶点。

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