Department of Cardiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
Gen Physiol Biophys. 2023 Mar;42(2):149-158. doi: 10.4149/gpb_2022061.
Studies have found that cardiomyocytes and cardiac fibroblasts (CFs) can communicate through exosomes, thereby affecting each other's biological functions, but there are few studies on the mechanism. miR-208a/b are specifically expressed in the heart and highly expressed in exosomes derived from various myocardial diseases. Hypoxia induced cardiomyocytes to secrete exosomes (H-Exo) with high expression of miR-208a/b. When H-Exo were added to CFs for co-culture, it was found that CFs took up exosomes, thereby upregulating the expression of miR-208a/b. H-Exo significantly promoted the viability and migration of CFs, enhanced the expression of α-SMA, collagen I and III, and promoted the secretion of collagen I and III. miR-208a or/and miR-208b inhibitors significantly attenuated the effects of H-Exo on CF biological functions. miR-208a/b inhibitors significantly enhanced the levels of apoptosis and caspase-3 activity in CFs, while H-Exo significantly attenuated the pro-apoptotic effects of miR-208a/b inhibitors. Further treatment of CFs with ferroptosis inducer Erastin found that H-Exo further enhanced the accumulation of ROS, MDA and Fe2+, the main indicators of ferroptosis, and inhibited the expression of GPX4, a key regulator of ferroptosis. miR-208a or/and miR-208b inhibitors significantly attenuated the effects of Erastin and H-Exo on ferroptosis. In conclusion, hypoxic cardiomyocyte-derived exosomes can regulate the biological functions of CFs through highly expressed miR-208a/b.
研究发现，心肌细胞和心脏成纤维细胞（CFs）可以通过外泌体进行通讯，从而影响彼此的生物学功能，但关于其机制的研究较少。miR-208a/b 特异性表达于心脏，在各种心肌疾病来源的外泌体中高表达。低氧诱导心肌细胞分泌高表达 miR-208a/b 的外泌体（H-Exo）。当将 H-Exo 加入 CFs 进行共培养时，发现 CFs 摄取外泌体，从而上调 miR-208a/b 的表达。H-Exo 显著促进 CFs 的活力和迁移，增强 α-SMA、胶原 I 和 III 的表达，并促进胶原 I 和 III 的分泌。miR-208a 或/和 miR-208b 抑制剂显著减弱了 H-Exo 对 CF 生物学功能的影响。miR-208a/b 抑制剂显著增强 CFs 中的凋亡水平和 caspase-3 活性，而 H-Exo 显著减弱了 miR-208a/b 抑制剂的促凋亡作用。进一步用铁死亡诱导剂 Erastin 处理 CFs，发现 H-Exo 进一步增加了 ROS、MDA 和 Fe2+的积累，这是铁死亡的主要指标，并抑制了铁死亡的关键调节因子 GPX4 的表达。miR-208a 或/和 miR-208b 抑制剂显著减弱了 Erastin 和 H-Exo 对铁死亡的影响。总之，低氧心肌细胞来源的外泌体可以通过高度表达的 miR-208a/b 调节 CFs 的生物学功能。
