Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Biochim Biophys Acta Mol Basis Dis. 2018 Nov;1864(11):3639-3649. doi: 10.1016/j.bbadis.2018.08.026. Epub 2018 Aug 22.
Diabetic cardiomyopathy (DCM) is characterized by cardiac microvascular endothelial cells (CMECs) injury and cardiomyocyte (CM) dysfunction. Exosomes mediated cellular communication between CMECs and CM has emerging roles in the pathogenesis of DCM, but the underlining mechanisms are unclear. Mammalian sterile 20-like kinase 1 (Mst1), a key component in Hippo pathway which participates in regulating organ size, apoptosis and autophagy, is involved in the development of DCM. We generated the endothelial-specific Mst1 transgenic mice (Tg-Mst1) and constructed diabetic model with streptozotocin (STZ). Interestingly, Tg-Mst1 mice suffered from worse cardiac function and aggravated insulin resistance compared with non-transgenic (NTg) diabetic mice. The content of Mst1 protein was increased, while Mst1 mRNA had no significant change in CM isolated from diabetic Tg-Mst1 mice. In vitro, CMECs-derived exosomes were taken up by CM and increased Mst1 protein content which inhibited autophagy, as well as enhanced apoptosis in high glucose (HG) cultured CM as evidenced by immunofluorescence and western blot analysis. In addition, Mst1 inhibited glucose uptake under diabetic condition by disrupting the glucose transporter type 4 (GLUT4) membrane translocation through decreasing the interaction between Daxx and GLUT4, as well as enhancing the association of Mst1 and Daxx. Our study exemplifies pleiotropic effects of Mst1-enriched exosomes released from CMECs on inhibiting autophagy, promoting apoptosis and suppressing the glucose metabolism in CM.
糖尿病心肌病（DCM）的特征是心脏微血管内皮细胞（CMECs）损伤和心肌细胞（CM）功能障碍。外泌体介导的 CMECs 和 CM 之间的细胞通讯在 DCM 的发病机制中具有重要作用，但潜在机制尚不清楚。哺乳动物无 sterile 20 样激酶 1（Mst1）是 Hippo 通路的关键组成部分，参与调节器官大小、细胞凋亡和自噬，与 DCM 的发展有关。我们生成了内皮细胞特异性 Mst1 转基因小鼠（Tg-Mst1）并构建了链脲佐菌素（STZ）诱导的糖尿病模型。有趣的是，与非转基因（NTg）糖尿病小鼠相比，Tg-Mst1 小鼠的心脏功能更差，胰岛素抵抗更严重。糖尿病 Tg-Mst1 小鼠 CM 中的 Mst1 蛋白含量增加，而 Mst1 mRNA 没有明显变化。在体外，CM 摄取了由 CMECs 衍生的外泌体，并增加了 Mst1 蛋白含量，抑制了自噬，同时通过减少 Daxx 和 GLUT4 之间的相互作用以及增强 Mst1 和 Daxx 的结合，增强了高糖（HG）培养的 CM 中的细胞凋亡。此外，Mst1 通过破坏葡萄糖转运蛋白 4（GLUT4）的膜转位，减少 Daxx 和 GLUT4 之间的相互作用，增强 Mst1 和 Daxx 的结合，抑制糖尿病状态下的葡萄糖摄取。我们的研究说明了富含 Mst1 的外泌体从 CMECs 释放对抑制自噬、促进细胞凋亡和抑制 CM 中葡萄糖代谢的多效性作用。
