MicroRNA-155调控动脉粥样硬化斑块内血管新生对易损斑块稳定性的影响与机制

Intra-plaque hemorrhage which caused by capillaries rupture is the most important trigger of plaque rupture.The rupture of capillaries is due to loss of support of smooth muscle cells. Searching therapies which can transfer angiogenesis to arteriogenesis is the key of reducing intra-plaque hemorrhage and plaque vulnerability.MiR-155 was reported as important modifiers during angiogenesis.However, previous results involving in the role in plaque progress and vulnerability are vacant. Using MiRNA Microarray Analysis and in situ hybridization, we demonstrated miR-155 was significantly expressed in Intra-plaque hemorrhage lesion of atherosclerotic plaque in human and mice.We speculate that miR-155 promotes angiogenesis and inhibits the shift from angiogenesis to arteriogenesis, resulting in intra-plaque hemorrhage and plaque vulnerability. Combined with double knock-out of Apo E and miR-155, local and systemic usage of Antagomirs, and study in human plasma and histological level of miR-155, we will detail the effect of miR-155 on plaque stability shift, so as to looking for new cytokines and transduction pathways related. The results of this study is expected to put forward mechanism study of plaque stability to a new point, as time as to develop new therapeutic targets.

动脉粥样硬化斑块内新生血管破裂导致斑块内出血是易损斑块破裂的触发因子。新生毛细血管的内皮细胞缺少平滑肌细胞支持是新生血管破裂的主要原因。使新生毛细血管内皮-平滑肌细胞协调生长是减少斑块内出血，降低斑块易损性的关键。miR-155在血管新生调控中起到重要作用，但其在动脉粥样硬化斑块内出血及斑块破裂中的作用及机制研究尚为空白。我们通过基因芯片及原位杂交等方法，在小鼠和人体标本中均证实miR-155在易损斑块/斑块内出血病变中显著高表达。因此提出假设：miR-155一方面促进斑块内血管新生，另一方面使新生血管的内皮-平滑肌细胞协同发育失调，抑制新生血管向成熟的小动脉转化，最终促进斑块内出血的发生。本课题拟应用基因敲除小鼠在体研究miR-155对动脉粥样硬化易损斑块新生血管成熟度的调控，并进一步研究其分子机制。本研究为揭示斑块内出血发生机制以及探索有效的稳定斑块治疗靶点具有重要意义。

动脉粥样硬化斑块内新生血管破裂导致斑块内出血是易损斑块破裂的触发因子。前期研究发现，microRNA-155在人和小鼠易损斑块/斑块内出血病变中显著高表达。本课题应用双基因敲除小鼠以及易损斑块动物模型，探索microRNA-155对小鼠易损斑块负荷、斑块稳定性、斑块成分、斑块内胶原酶水平和促炎症因子水平的影响。并深入研究其对斑块内新生血管、斑块内出血，斑块中VEGF-A、VEGFR1表达的影响。并得出结论：microRNA-155通过增加斑块内新生血管、斑块内出血发挥促动脉粥样硬化的作用。. 本课题还应用microarray以及生物信息学技术，明确了在动脉粥样硬化进展以及斑块破裂伴血栓形成过程中起重要调控作用的microRNAs, 并深入挖掘其靶基因和富集通路。研究发现了22个microRNA在动脉粥样硬化病变血管中显著差异表达，其中miR-322-5p（上调）和miR-206-3p（下调）最为显著。发现了11个microRNAs在斑块破裂过程表达显著升高，其中miR-466h-5p最为显著。本研究为探索新的动脉粥样治疗靶点提供科学理论根据，为下一步研究工作开辟了新的研究方向。