IDO1及其代谢产物犬尿氨酸对病理性心肌肥厚的作用与机制研究

Cardiac hypertrophy is an important pathophysiological process of heart failure, but its specific mechanism is not yet fully understood. Kynurenine is a metabolite of the amino acid L-tryptophan via indoleamine 2,3 bisoxygenase（IDO）. Previous research and our preliminary studies suggest that kynurenine has a significant correlation with cardiovascular disease and heart failure. Applicants'studies during postgraduate suggested that loss of IDO1 could protect mice from high-fat diet-induced obesity. At the same time, our studies show that IDO1 and its metabolites, kynurenine, were involved in pressure overload induced cardiac hypertrophy. However, the detailed mechanics was unknown. AhR is a kynurenine receptor. The literature shows that AhR are involved in myocardial pathological injury. We hypothesized that kynurenine may be involved in the pathophysiological process of cardiac hypertrophy after binding to the AhR. This project will use IDO1 knockout mice, IDO1 specific inhibitors and viral packaging and recombinant technology to clarify IDO1-derived kynurenine involved in cardiac hypertrophy and to elucidate the molecular mechanisms of pathological process. The study will provide new ideas for the treatment of heart failure.

心肌肥厚是心衰的重要病理生理过程，但其具体机制尚未完全明了。犬尿氨酸主要由色氨酸经吲哚胺2，3双加氧酶（IDO）代谢而来。现有研究以及前期实验提示犬尿氨酸与心血管疾病以及心衰有着显著的相关性。申报者研究生期间研究提示IDO1基因敲除能够保护小鼠高脂饮食诱导的肥胖。同时前期实验证明IDO1及其代谢产物犬尿氨酸参与压力负荷导致的心肌肥厚。AhR是犬尿氨酸受体。文献表明芳香烃受体(AhR)参与到心肌的病理损伤。我们推测，犬尿氨酸可能通过与AhR结合后，调控靶基因表达，参与心肌肥厚的病理生理过程。本项目将利用IDO1基因敲除小鼠、IDO1特异性抑制剂以及病毒包装重组技术等，从动物、细胞、分子三个层面，阐明IDO1代谢产物犬尿氨酸通过AhR及其下游通路参与心肌肥厚的病理生理机制。该研究将加深心肌肥厚的发病机制的认识，为进一步防治心力衰竭提供新的线索。