硫氧还蛋白相互作用蛋白在糖尿病心肌缺血后血管新生中的作用及机制

Collateral vessel growth is a compensatory mechanism in response to the ischemia created by advanced coronary artery disease to rescue ischemic myocardium. However, Diabetes-induced impairment of collateral formation has been demonstrated in subjects with coronary artery disease, which may contribute to unfavorable prognosis among diabetic individuals. The underlying mechanism remains to be elucidated. The paradigm of Thioredoxin (Trx) system as endogenous antioxidant has shifted in recent times with Trx activity proven to extend to many aspects of vascular function, including endothelial cell homeostasis and key angiogenic process. In our previous studies, Trx activity was shown to be decreased in diabetic cardiac tissues even before ischemia, which may mediate the disordered angiogenesis manifested in myocardium, but the reason of Trx inactivation and its downstream pathway still need to be identified. Thioredoxin-interacting protein (TXNIP), as Trx endogenous inhibitor, is strongly induced by glucose due to a carbohydrate response element within its promoter, and increased interaction between TXNIP and Trx could be of consequence to the inhibition of Trx activity. Based on recent reports, TXNIP is implicated in the injury of pancreatic islet β cells and the pathogenesis of diabetes mellitus through inflammasome activation. It is still unknown whether TXNIP is related with diabetes-induced impairment of angiogenesis in ischemic myocardium. Thus we hypothesize that inhibition of Trx by enhanced TXNIP expression in endothelial cells may play a pivotal role in hyperglycemia-induced impairment of angiogenesis and thereby exacerbated myocardial injury, which will be investigated both in vivo and in vitro by means of genetic modulation and molecular imaging. TXNIP may be a novel target to identify strategic therapeutic modality that ultimately improves quality of life and mitigates disease progression in diabetic individuals with coronary artery disease.

糖尿病可显著抑制冠心病患者缺血心肌的代偿性血管新生，加重心肌损伤，但具体机制不清。氧化还原调节分子硫氧还蛋白（Trx）促进血管新生的作用日益受到关注，我们的前期研究发现，糖尿病心肌组织的Trx活性显著降低，这可能是糖尿病影响缺血心肌血管新生的重要原因，其上下游的分子机制亟待阐明。作为Trx的内源性抑制分子，Trx相互作用蛋白（TXNIP）的启动子序列含有碳水化合物反应元件，高糖可促进其转录表达，最新研究表明，TXNIP介导的胰岛β细胞损伤在糖尿病发生发展中占有关键地位。糖尿病对缺血心肌血管新生的影响是否也与TXNIP有关呢？目前国内外尚未见报道。由此提出本课题设想：糖尿病通过增加TXNIP的表达抑制Trx活性影响内皮细胞血管新生能力，进而影响缺血心肌的血管新生。拟采用TXNIP基因干预的方式，利用在体及离体实验，结合分子影像等前沿技术证实这一设想，为糖尿病合并冠心病的防治提供新靶点。

糖尿病可显著抑制冠心病患者缺血心肌的代偿性血管新生，加重心肌损伤，但具体机制不清。硫氧还蛋白相互作用蛋白（Thioredoxin-interacting protein，TXNIP）作为近些年在糖尿病研究领域的热点分子，其转录及表达受血糖调控，它所介导的胰岛β细胞损伤在糖尿病发生发展中占有关键地位，糖尿病对缺血心肌血管新生的影响是否也与TXNIP有关呢？其下游的分子机制又是什么呢？目前国内外均未见报道。本研究利用在体及离体实验，采用基因干预手段发现，糖尿病通过增加TXNIP的表达抑制缺血心肌的血管新生。Wnt/β-catenin在血管发育及血管新生中的作用日益受到关注，而且重要的是，在缺血心肌的冠脉内皮细胞中β-catenin的核转位明显增加，预示了在Wnt/β-catenin缺血心肌血管新生中的重要作用。我们进一步的研究发现，糖尿病条件下，TXNIP表达增加可以引起ROS生成增加及Wnt/β-catenin信号通路活性下降，使得心肌内皮细胞血管生成能力受损，最终导致缺血心肌血管生成减少，心肌缺血损伤加重。本研究首次发现TXNIP表达增加抑制Wnt/β-catenin通路是糖尿病抑制缺血心肌血管新生的重要原因，为糖尿病加重心肌缺血损伤提供了新的理论基础，为糖尿病合并冠心病患者的治疗提供了新的干预靶点，对于改善这类患者的预后具有重要的现实意义。