HFABP促进糖尿病和非糖尿病时冠状动脉支架内再狭窄和机制研究

The morbidity ratio of coronary artery in-stent restenosis (ISR) is higher in diabetic patients than non-diabetic patients, with mechanism remain not fully unknown. In our previous study, we established diabetic and non-diabetic minipig models of ISR, and found that many proteins of proliferation, migration and pro-inflammation were increased, including HFABP (heart-type fatty acid binding protein). Based upon study of mRNA chip, proteomics and cellular experiments, we have discovered that aortic smooth muscle cells (ASMCs) of HFABP overexpression, or stimulated by recombinant HFABP display significant increase of growth, migration, remodeling and pro-inflammatory reaction. HFABP binds TLR-4, and the effects of HFABP require mediation of TLR-4 and nuclear receptor NR4A3. Collectively, these results suggest that increased HFABP is related to post-injury vascular neointimal hyperplasia and ISR, which is aggrevated in diabetic status. Next, we will investigate whether HFABP promotes post-injury vascular neointimal hyperplasia in wide-type and genetically modified mice (HFABP-KO, TLR-4-KO and NR4A3-KO) with diabetes and non-diabetes. HFABP effects will be analyzed in cell experiments with mechanism clarification.

糖尿病时冠脉支架内再狭窄（ISR）发病率高但机制了解有限。我们建立糖尿病和非糖尿病小型猪冠脉ISR模型，发现ISR组织中HFABP（heart-type fatty acid binding protein）等蛋白水平比对照显著升高。mRNA芯片检查、蛋白组学和细胞实验发现，主动脉平滑肌细胞（ASMCs）内表达HFABP和用HFABP重组蛋白刺激显著促进细胞迁移、增殖、重构和炎症。HFABP能结合TLR-4，其生物学作用需TLR-4和核受体NR4A3 介导。结合文献提示HFABP与动脉损伤后内膜增生和ISR有关，且当合并糖尿病时效应更明显。后续将行体内体外实验，运用糖尿病和非糖尿病时野生型、HFABP-KO、TLR-4-KO和NR4A3-KO等小鼠探讨HFABP是否促进动脉内膜损伤后增生，明确致病途径和机制。探讨 HFABP对ASMCs作用、信号通路影响和机制，为可能的临床转化提供资料。

糖尿病时冠脉支架内再狭窄（ISR）发病率高但机制了解有限。我们建立糖尿病和非糖尿病小型猪冠脉ISR模型，发现ISR组织中HFABP（heart-type fatty acid binding protein）等蛋白水平比对照显著升高。mRNA芯片检查、蛋白组学和细胞实验发现，主动脉平滑肌细胞（ASMCs）内表达HFABP和用HFABP重组蛋白刺激显著促进细胞迁移、增殖、重构和炎症。HFABP能结合TLR-4，其生物学作用需TLR-4和核受体NR4A3 介导。结合文献提示HFABP与动脉损伤后内膜增生和ISR有关，且当合并糖尿病时效应更明显。后续将行体内体外实验，运用糖尿病和非糖尿病时野生型、HFABP-KO、TLR-4-KO和NR4A3-KO等小鼠探讨HFABP是否促进动脉内膜损伤后增生，明确致病途径和机制。探讨 HFABP对ASMCs作用、信号通路影响和机制，为可能的临床转化提供资料。