内皮型一氧化氮合酶调控弥漫性冠心病术后靶血管再狭窄的新机制

Mortality after conventional coronary artery bypass grafting remains high in patients with diffuse right coronary artery disease. To improve patient outcome, we first developed a new surgical technique, selective coronary vein bypass grafting (SCVBG). In SCVBG, the middle cardiac vein (MCV) was selected as the target vessel and the graft vessel was anastomosed to the MCV. We used SCVBG to treat 75 patients with diffuse disease. The 5-year survival of the 75 patients was 90%. Their follow-up examination showed that using artery graft in SCVBG resulted in substantially better long-term patency in the MCV than using vein graft. Our previous NSFC project demonstrated that artery grafts secreted vasoactive factors such as eNOS, which inhibits proliferation of vessel smooth muscle cell by down-regulating MAPK. We therefore hypothesize that the duplex intervention--inhibition of MAPK as well as the activation of eNOS--may potentially ameliorate MCV restenosis. A rabbit model of jugular venous arterialization will be applied to stimulate MCV restenosis. The duplex regulation will be accomplished by using the inhibitor of MAPK signal pathway, the impact on the expression of eNOS in smooth muscle cell will decrease as well as simultaneous the transfection of eNOS plasmid in smooth muscle cell and endothelial cell will be done to increase the release vasoactive substances. Moreover, we will further testify in vitro style thus to provide the more evidence for elucidation of the mechanism and confirmation of action targets.

弥漫性右冠脉病变施行常规搭桥术死亡率高；我们率先采用选择性心中静脉动脉化手术（SCVBG）治疗75例患者五年生存率达90%；随访发现选择乳内动脉桥其下游靶血管（心中静脉）通畅率远高于选择静脉桥的靶血管。前期国自然研究发现，乳内动脉桥可表达eNOS并释放血管活性因子，是减缓靶血管再狭窄的因素之一。预实验模拟靶血管平滑肌细胞的牵张刺激，MAPK通路相关基因表达升高；近年发现，MAPK可调控eNOS表达并与血管增殖有关。遂提出“抑制MAPK并活化eNOS，双重干预减轻心中静脉再狭窄”的假说。本课题拟采用兔颈静脉动脉化模型模拟SCVBG术后靶血管再狭窄，通过MAPK信号通路抑制剂减轻其对血管平滑肌细胞eNOS表达的影响，同时对靶血管进行eNOS转染活化，增加其血管活性物质释放，双重手段抑制靶血管再狭窄。此外，通过体外实验进一步验证不同处理方式的作用机制，为阐明靶血管再狭窄机制及明确干预靶点提供依据

右冠状动脉（RCA）弥漫性冠脉病变（DCAD）是冠心病外科诊疗中的难点，选择性心中静脉动脉化（SCVBG）可以完成常规手术无法完成的冠脉血运重建，但目前对于SCVBG的实际诊疗效果尚不明确，且影响SCVBG术后疗效的因素及作用机制也需进一步探究。为此，本课题研究过程中：①首先采用回顾性临床研究，探究了SCVBG对于无法行CE的RCA系统严重DCAD患者的围术期和远期MACCE事件等并发症发生率的差异及其对远期生存率的影响，结果显示SCVBG对于无法行CE的RCA系统严重DCAD患者，是一种理想的手术方式，同时临床回顾性研究发现SCVBG桥血管材料与术后靶血管通畅率选择是影响DCAD诊疗效果的重要因素，且二者间存在明显相关性；②固接下来我们着重探讨了动脉桥血管预防靶血管再狭窄的机制，同时探究能否通过eNOS转染静脉桥血管，预防SCVBG术后靶血管再狭窄。. 最终发现靶血管术后通畅率是决定SCVBG手术疗效的重要因素，术中采用动脉作为吻合于MCV的桥血管选材，可以提高术后靶血管术后通畅率，动脉桥血管提高靶血管通畅率的机制主要有两点：一是动脉桥血管可以通过自身主动收缩抑制由于血流剪切力升高引起的靶血管损伤，二是动脉桥血管通过自身主动分泌eNOS抑制再狭窄相关通路活化，进而抑制SCVBG术后靶血管再狭窄；通过静脉桥血管转染eNOS，使静脉桥血管高表达eNOS可以在一定程度上抑制血流剪切力引起的靶血管损伤，也可以抑制再狭窄相关通路活化，但效果较使用动脉桥血管时略差。上述成果为SCVBG这一术式的有效性提供了有力证据，同时探究了动脉桥血管材料通过稳定血流动力学参数，调控eNOS表达预防靶血管远期再狭窄的机制，为提高RCA弥漫性病变手术疗效提出了新方法、新思路。