Department of Respiratory and Critical Care Medicine, Respiratory Disease Research Institute, The First Affiliated Hospital, Fujian Medical University, NO 20, Chazhong road, Taijiang district, Fuzhou, Fujian Province, 350005, People's Republic of China.
Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
Sleep Breath. 2024 Mar;28(1):319-329. doi: 10.1007/s11325-023-02920-2. Epub 2023 Sep 19.
Exosomes are involved in cell-to-cell communication in numerous diseases including cardiovascular diseases, neurological diseases. Little attention has been dedicated to exosomal circular RNAs in obstructive sleep apnea (OSA)-related cardiovascular diseases. The aim of this study was to explore the role of exosomal circular RNA ZNF292 (circZNF292) on AC16 cells exposure to intermittent hypoxia (IH).
Exosome release inhibitor GW4869 was used to examine the effect of exosomes on IH-induced AC16 cells apoptosis. The expression of exosomal circZNF292 was detected by qRT-PCR in AC16 cells exposure to IH, and a luciferase reporter assay was conducted to confirm the connection between circZNF292 and miR-146a-5p. Exosomal circZNF292 was stably transfected with short hairpin RNAs (shRNAs) against circZNF292 and co-cultured with AC16 cells. The expression of miR-146a-5p and apoptosis-related protein was then measured to evaluate the effect of exosomal circZNF292.
We found that IH contributed to the AC16 cells apoptosis, and the administration of GW4869 increased the apoptosis of cardiomyocytes when exposed to IH. The expression of exosomal circZNF292 decreased and miR-146a-5p increased significantly in AC16 cells exposed to IH compared to normoxic conditions. Bioinformatics analysis predicted a circZNF292/miR-146a-5p axis in IH-induced cardiomyocytes apoptosis. The dual-luciferase reporter system validated the direct interaction of circZNF292 and miR-146a-5p. Knockdown of circZNF292 increased the expressions of miR-146a-5p and accelerated the AC16 cardiomyocytes apoptosis.
The findings of this study suggested a novel mechanism by which exosomes transmit intrinsic regulatory signals to the myocardium through the exosomal circZNF292/miR-146a-5p axis. This finding highlights the potential of targeting this pathway as a therapeutic approach for treating cardiovascular diseases associated with OSA.
外泌体参与包括心血管疾病、神经疾病在内的多种疾病的细胞间通讯。在阻塞性睡眠呼吸暂停（OSA）相关心血管疾病中，人们对外泌体环状 RNA（circRNA）的关注甚少。本研究旨在探讨外泌体环状 RNA ZNF292（circZNF292）在 AC16 细胞暴露于间歇性低氧（IH）中的作用。
使用外泌体释放抑制剂 GW4869 检测外泌体对 IH 诱导的 AC16 细胞凋亡的影响。通过 qRT-PCR 检测 IH 作用下 AC16 细胞中外泌体 circZNF292 的表达，并通过荧光素酶报告实验证实 circZNF292 与 miR-146a-5p 的连接。用针对 circZNF292 的短发夹 RNA（shRNA）稳定转染外泌体 circZNF292，并与 AC16 细胞共培养。然后测量 miR-146a-5p 和凋亡相关蛋白的表达，以评估外泌体 circZNF292 的作用。
我们发现 IH 导致 AC16 细胞凋亡，并且当暴露于 IH 时，GW4869 的给药增加了心肌细胞的凋亡。与常氧条件相比，IH 作用下 AC16 细胞中外泌体 circZNF292 的表达降低，miR-146a-5p 的表达显著增加。生物信息学分析预测了 IH 诱导的心肌细胞凋亡中 circZNF292/miR-146a-5p 轴。双荧光素酶报告系统验证了 circZNF292 和 miR-146a-5p 的直接相互作用。circZNF292 的敲低增加了 miR-146a-5p 的表达并加速了 AC16 心肌细胞的凋亡。
本研究结果表明，外泌体通过外泌体 circZNF292/miR-146a-5p 轴将内在调节信号传递到心肌，从而提供了一种新的机制。这一发现强调了靶向该途径作为治疗与 OSA 相关心血管疾病的潜在治疗方法的重要性。
