内皮细胞HSPA12B对心脏老化的延缓作用及机制研究

The decline of mitochondrial function due to decrease of mitochondrial biogenesis is important for the development of cardiac aging. Evidence demonstrated that ‘miR-217/SIRT1/PGC-1α’ signaling is critical for the activation of mitochondrial biogenesis..HSPA12B is expressed specifically in endothelial cells. During the previous NSFC experiments, we observed that overexpression of HSPA12B in endothelial cells attenuates cardiac hypertrophy and increases diastolic function in aged mice. Our pilot data also indicate that this action of endothelial HSPA12B could be mediated by decreasing endothelial cell-derived exosome loaded miR-217, which in turn removes the inhibition of ‘SIRT1/PGC-1α/mitochondrial biogenesis’ signaling axis and improves mitochondrial function in cardiomyocytes. .To test this posibility, we will examine the cardiac aging in aged HSPA12B transgenic and HSPA12B knockout mice. We will also investigate whether the ‘exosome/miR-217/SIRT1/PGC-1α/mitochondrial biogenesis’ signaling axis mediates the action of HSPA12B using cell co-culture models.The results will provide novel clues for discovering potential targets of retarding cardiac aging based on inter-cellular signals.

线粒体合成减少导致的线粒体功能减退是心脏老化的重要原因，而‘miR-217/SIRT1/PGC-1α’信号对线粒体合成至关重要。.HSPA12B是特异性表达于血管内皮细胞的基因。在前2项国家自然基金研究中，我们发现：内皮细胞HSPA12B不仅改善老年鼠心脏肥大和舒张功能(心脏老化特征)，且该作用可能是通过“减少exosome负载的miR-217含量、解除其对心肌细胞‘SIRT1/PGC-1α/线粒体合成’信号的抑制，纠正因增龄引起的心肌线粒体合成障碍”而介导的。.本项目将在前期工作基础上，采用HSPA12B转基因鼠、敲除鼠，综合评价内皮细胞HSPA12B对心脏老化的延缓作用，并结合细胞培养模型，阐明 ‘exosome/miR-217/SIRT1/PGC-1α/线粒体合成’信号系统在其中的作用，以明确其保护机制。研究结果将从细胞间信号影响线粒体合成的角度，为延缓心脏老化提供新的思路。

内皮细胞损伤德海心脏衰老的重要因素之一。热休克蛋白A12B (heat shock protein A12B, HSPA12B)是一个内皮细胞特异性表达的热休克蛋白。然而HSAP12B在心脏衰老中的作用尚不清楚。本研究中，我们发现衰老心脏中HSPA12B表达下降， 而过表达HSPA12B则显著改善老龄鼠心脏功能、降低衰老标志物表达，同时减少ROS产生、增加线粒体合成、促进血管新生和脂肪酸氧化。过表达HSPA12B也增加老龄鼠PGC-1表达。体外研究发现，内皮细胞过表达HSAP12B后，可显著增加PGC-1表达、并促进其向内皮细胞的细胞核移位，值得注意的是，内皮细胞的HSAP12B可通过旁分泌机制改善衰老心肌细胞的收缩能力。更为重要的是，以PGC-1特异性抑制剂SR-18292处理内皮细胞后，过表达HSPA12B对衰老心肌细胞功能的改善作用消失。这些结果提示，内皮细胞过表达HSPA12B通过PGC-1依赖性机制旁分泌调控心肌细胞衰老。HSPA12B是一个心肌的心脏衰老的负性调控基因，靶向增加HSPA12B可能是延缓心脏衰老的潜在措施之一。