心肌代谢小分子L-肉碱对冠状动脉微栓塞后微血管新生的影响及机制

Coronary microvascular dysfunction significantly influences the clinical prognosis of several cardiac diseases. Microvascular angiogenesis after microcirculation injury is the key to maintain cardiac function. Previous studies suggested that microvessel underwent self-function alteration via sensing metabolites changes in myocardial microenvironment. However, it was unclear whether metabolites could stimulate microvascular angiogenesis. In our previous work, we confirmed a few of microvascular angiogenesis after coronary microembolization, which could not reverse cardiac dysfunction. We also found myocardial level of L-carnitine was decreased significantly in metabonomics analysis. In vitro, L-carnitine could promote VEGF expression and NO release in cardiac microvascular endothelial cells. Therefore, we supposed L-carnitine may increase microvasuclar angiogenesis. In this study, mice coronary microembolization model with differential expression of carnitine palmitoyltransferase were developed to clarify the impact and mechanism of L-carnitine on microvascular angiogenesis and myocardial metabolism. Meanwhile, the mechanism of L-carnitine on microvascular endothelial cells’ growth and angiogenesis was also clarified in vitro level. Finally, we will elaborate the role of L-carnitine on microvascular occlusion and cardiac events on coronary no reflow patients after primary coronary intervention. Above all, these things will provide novel evidence for the diagnosis and treatment of coronary microvascular dysfunction.

冠状动脉微循环功能障碍，严重影响多种心血管疾病的预后。微循环阻塞后的微血管新生是代偿心脏功能的关键之一。既往发现，微血管可感知心肌代谢产物的变化并调节自身功能，但代谢小分子能否影响微血管新生，尚不明确。课题组前期在小鼠冠脉微栓塞模型中发现少量微血管新生，但不足以代偿心功能障碍；心肌代谢组学发现多种代谢小分子改变，其中L-肉碱显著减少；体外应用L-肉碱刺激心肌微血管内皮细胞，显著促进NO释放及VEGF表达，推测L-肉碱可能促进冠脉微血管的新生。本课题拟构建基因敲除肉碱脂酰转移酶（CPT）的小鼠冠脉微栓塞模型，结合心肌PET核素检查，探索L-肉碱对微血管新生和心肌代谢的影响及机制；在心肌微血管内皮细胞水平，明确L-肉碱在微血管内皮细胞生长、成血管反应中的分子机制。同时，在冠脉无复流的临床队列中探索L-肉碱水平对微血管阻塞、临床心血管预后的影响。进而为改善冠脉微血管障碍所致的心肌损伤提供新思路。

脂肪酸代谢是心肌能量供应的重要方式之一，而肉碱作为一种类氨基酸的代谢小分子，可促进线粒体内的长链脂肪酸的氧化，进而为心肌代谢提供重要能源。冠状动脉微循环是维持心肌能量代谢的关键，肉碱能否通过影响血管新生进而改善心脏功能尚不明确，本次课题主要通过动物和细胞实验的方式，明确证实了肉碱在心肌微血管功能障碍中的作用机制和治疗价值（从心肌微血管灌注功能、内皮细胞屏障功能、炎症反应及亚细胞结构等多方面阐述了左旋肉碱改善糖尿病心肌微循环功能障碍的作用）；同时在心力衰竭队列中阐明血清肉碱的表达水平，及其对患者远期预后的预测价值。本课题共培养博士研究6名，发表学术论文13篇（均标注课题基金号），其中SCI论文10篇，最高IF=17分；中文核心论著3篇；参加国内外学术会议交流4次；获得科技奖项2项；授权实用新型专利1项。