血管内皮细胞源性的miR-29a通过对血管平滑肌细胞表型的调节参与急性Stanford A型主动脉夹层发病机制的研究

Acute Stanford type A aortic dissection (AAAD) is an acute and severe disease that is endangering human beings. Although its miRNA expression profile has been reported, the role of miRNA in its pathogenesis remains unclear. Hypertension-induced AAAD (HAAAD) is the most predominant patient group. We had found that miR-29a was significantly overexpression in HAAAD serum. With literature review and target prediction, we found KLF4 was the downstream target of miR-29a, and YAP can regulate the synthesis of miR-29a. HAADAD. Our previous work on the tissue from HAAAD found miR-29a and YAP was overexpression in aortic wall intima, miR-29a overexpression and YAP, KLF4 down-regulation was also found in the aortic wall media. And all the differential expression was correlated with the phenotype switch of vascular smooth muscle cells. Further experiments showed that endothelial Cell-derived miR-29a is involved in the regulation of smooth muscle cell phenotypes switch with exosome trafficking miR-29a into smooth muscle cells. Therefore, we hypothesized that hypertension can over-express the YAP of endothelial cells, promote miR-29a’s synthesis by endothelial cells and miR-29a can be secretion as exosomes, and through these exosomes miR-29a will transferred into smooth muscle cells, by the inhibiting effect of miR-29a on KLF4, miR-29a can promote smooth muscle cell phenotype switching, finally promote the occurrence of HAAAD. The project is expected to make it clear that miR-29a derived from vascular endothelial cells can play a regulatory role in the pathogenesis of HAAAD through the regulation of KLF4 in smooth muscle cells. It can provide a new theoretical basis for the pathogenesis of HAAAD and provide a novel idea for clinical treatment.

急性Stanford A型主动脉夹层（acute Stanford type A aortic dissection， AAAD）是严重危害人类的急重症，尽管其miRNA表达谱已有报道，但miRNA在发病机制中的作用仍不明确。通过高血压诱发的AAAD（HAAAD），我们发现血清内miR-29a高表达，文献及靶点预测示其靶点为KLF4，而YAP可调节miR-29a的表达。发现破口处组织内膜miR-29a、YAP高表达，中层miR-29a高表达而YAP、KLF4低表达，且与血管平滑机细胞表型转换相关；细胞实验发现内皮细胞源的miR-29a可通过外泌体转至平滑肌细胞内并调节平滑肌细胞表型。因此，我们推测高血压可使内皮细胞YAP过表达，促进miR-29a合成及分泌，并通过外泌体进入平滑肌细胞抑制KLF4表达，促进平滑肌细胞表型转换，促进HAAAD的发生。预期可为夹层发病提供新理论依据和新思路。

研究内容及目标方面：通过本项研究，在夹层患者主动脉组织及动物实验水平明确，circ_TGFBR2 在急性 Stanford A 型主动脉夹层下调，机制研究显示，circ_TGFBR2的下调减弱了对 miR-29a 的吸附作用，进而导致 miR29a 对 KLF4 的抑制作用增强，导致 VSMCs 由收缩型向增值分泌型转换增加，促进夹层的发生及发展。过表达 circ_TGFBR2 可通过 circ_TGFBR2-miR-29a-KLF4 途径逆转 VSMCs 表型转换，抑制主动脉夹层的发生发展。该结果再次证实VSMCs表型转换在主动脉夹层发病中具有重要调节作用，与既往文献发表的大量研究结果一致，但本次研究发现circ_TGFBR2-miR-29a-KLF4具有调节VSMCs表型转换，参与主动脉夹层发病机制调节的作用，尚无文献报道，具有一定的原创性与创新性。通过本研究发现circ_TGFBR2及miR-29a作为主动脉夹层的治疗靶点存在理论可行性及理论基础，具有一定的临床运用前景。在HAAAD患者组织水平、HA-VSMCs细胞机制研究水平及动物模型水平完成了既定研究内容及研究目标。.在研究结果及成果方面：在本项研究经费支持下，项目组成员共计发表SCI论文3篇；项目组成员周泽奕、何孝军顺利毕业并获取博士学位；潘亮、艾力牙硕士毕业，并继续攻读博士学位。完成既定的考核目标。