非eNOS途径在ADMA致内皮祖细胞损伤中的作用及机制研究

Retarded re-endothelialization due to endothelial progenitor cell (EPC) dysfunction contributes greatly to delayed vascular repair and restenosis after stent implantation. Results from both foreign and our studies have confirmed that the asymmetric dimethylarginine (ADMA) is an important risk factor that decreases the function of EPC. Although the eNOS/NO pathway has been considered as the key mechanism for the actions of ADMA, it may not be sufficient to explain the damaging effects exerted by ADMA in a complete way. Based on our investigative study and foreign literature review, we propose a novel concept that endoplasmic reticulum (ER) stress is the most likely cause that is independent of eNOS/NO pathway for ADMA-induced EPC dysfunction. Thus, in this study, we intend to elucidate the role of ER stress in ADMA-induced EPC dysfunction at the cellular level, and then by using animal models as well as gene knock-out approaches, confirm that ER stress is the key mechanism responsible for ADMA-induced EPC dysfunction and retarded re-endothelialization which is independent of eNOS/NO pathway. Findings of this scheduled study may be expected to increase the possibility of achieving a breakthrough in prevention of restenosis.

内皮祖细胞（EPC）功能降低所致的再内皮化延迟是影响支架植入后内皮修复及再狭窄的重要原因。国外学者及我们的研究均确证非对称二甲基精氨酸（ADMA）是致EPC功能降低的关键因素。虽然eNOS/NO途径是介导ADMA作用的重要机制，但仍不能完全解释ADMA的损伤作用。我们结合文献及探索性研究提出：内质网应激可能是eNOS/NO途径之外调控ADMA致EPC功能损伤的新机制。故本研究拟在细胞水平阐明内质网应激途径在ADMA诱导的EPC功能损伤中的作用，并运用动物模型及基因敲除等手段，进一步确证内质网应激是eNOS/NO途径之外介导ADMA致EPC功能损伤及再内皮化进程延迟的关键途径。本研究将有望为突破再狭窄防治的瓶颈提供新思路。

冠心病患者内皮祖细胞（EPC）功能降低是影响支架植入后内皮修复和导致再狭窄的重要原因，既往研究表明内源性一氧化氮合酶（NOS）抑制物非对称二甲基精氨酸（ADMA）是致EPC功能降低的关键因素，但ADMA是否通过非eNOS通路影响EPC功能尚未可知。在本项目资助下，我们探讨了内质网应激和自噬在ADMA致EPC损伤中的作用及机制，发现ADMA可直接触发内质网应激并介导EPC迁移和粘附功能的损伤；同时，我们亦证实ADMA可通过Akt/mTOR通路上调EPC自噬水平从而影响其迁移和成管能力。上述研究证实ADMA可通过非eNOS途径影响EPC功能、干扰血管损伤后再内皮化进程。此外，在本项目资助下，我们亦证实AIBP通过SREBP2和Notch1通路调控生血内皮造血及动脉粥样硬化性心血管疾病、miR-199介导了硝酸甘油耐受的表观遗传学机制、miR-15b-5p通过AKT3调控调控冠脉侧支循环的形成、外泌体miR-125b和内皮细胞来源的miR-185-5p在心梗后心肌修复中发挥重要作用。这些研究成果有望为提高EPC修复血管能力，加速支架内再内皮化进程从而防治晚期血栓和缺血性心脏病的防治提供新的理论依据和新思路。