PC1调控平滑肌细胞表型转化在促进主动脉夹层形成中的作用及其机制研究

主动脉夹层（AD）是一种致死率极高的疾病，胶原纤维沉积可能在AD的发生过程中起到重要作用。我们前期工作显示：AD来源血管平滑肌细胞（SMC）向合成型转化并低表达PC1基因；上调合成型SMC PC1表达可使其向收缩型转化；下调收缩型SMC PC1表达可使其向合成型转化，合成胶原纤维增多；PC1下调通过激活mTOR信号通路作用于SMC，雷帕霉素可阻断PC1下调对SMC表型的调控作用。而PC1下调是能否导致AD发生仍不清楚。既往文献报道PC1基因常规敲除后小鼠在胚胎时期即由多种原因而死亡。我们此次拟通过时空特异性基因敲除，仅在小鼠出生后敲除SMC中PC1的表达，观察主动脉SMC是否向合成型转化并上调合成胶原纤维？能否形成AD？雷帕霉素能否阻断SMC向合成型转化并预防AD发生？从而阐明PC1下调表达、SMC表型转化和AD发生之间的因果关系,为探索AD的发病机制、寻找早期诊断与治疗方法提供理论依据。

Aortic dissection (AD) was a lethal disease with an extraordinary high rate of mortality. Excessive secretion and deposition of collagen may play a pivotal role in the pathogenesis of AD. Our previous work has shown that: Vascular smooth muscle cells (vSMCs) from AD specimen had converted into a synthetic phenotype and the PC1 gene was down regulated. Upregulation of PC1 could turn the vSMCs from a synthetic phenotype into a contractile one. While down regulation of PC1 would turn the vSMCs from a contractile phenotype into a synthetic one and increase its function of synthesis and secretion of collagen. PC1 regulates the phenotype change and function of vSMCs via the mTOR signal pathway. The effect of PC1’s down regulation to modulate vSMCs’ phenotypic transformation could be blocked by rapamycin. However, it remains unclear whether the down regulation of PC1 could directly arouse the formation of AD. Literature had previously reported that the routine homozygous PC1 gene knockout mice totally died in the embryonic period due to variety of reasons. We plan to apply the time and spatial specific gene knockout technology. Hence the knock out of the PC1 gene exclusively occur in vSMCs and turn into effect only after birth by the induction of tamoxifen. We intend to observe whether vSMCs from this model could convert into a synthetic phenotype and increase its function to synthesis and secret of collagen? Whether the down regulation of PC1 could directly result in the formation of AD? Whether rapamycin can block vSMCs change into synthetic phenotype and further prevent the occurrence of AD? Thereby attempt to clarify the causal relationship among PC1 down regulation, vSMCs phenotype change and formation of AD. This work may attribute to explore the pathogenesis of AD and thus provide a theoretical basis for early diagnosis, prevention and treatment.