氧化低密度脂蛋白调控凝集素样氧化低密度脂蛋白受体-1介导早期心肌重构的机制研究

The oxidative modification of (low-density lipoprotein) LDL cholesterol to ox-LDL and the upregulation of its receptor (Lectin-like oxidized low-density lipoprotein receptor-1, LOX1) have been thought to be a key initiating step in the development of atherosclerosis. However, few reports focused on the effect of ox-LDL on the myocardium. We observe that the increasing plasma ox-LDL level is associated with increased thickness of left ventricular wall from a random sample of about 100 volunteers. So we plan to analyze sample from more volunteers to test whether ox-LDL or its soluble receptor (sLOX1) is a risk marker for early myocardium remodelling. In animal study, we observe that ox-LDL induces cardiac hypertrophy and upregulated AT1R expression by LOX1. We will study whether ox-LDL-LOX1 induces cardiac remodelling by regulation AT1R signal and NF-κB is involved the process by downregulation and overexpression of LOX1 or AT1R in vitro and in vivo. To explore whether the effect is dependent of Angtension II, We next study the mechanism in angiotensionogen knockout (ATG-KO) mice. The study will be an effective "proof of concept" that ox-LDL impacts cardiac structure and function independent of classic risk factors including prevalent vascular damage. It suggest that ox-LDL is a risk marker for early myocardium remodelling.

我们在最近研究观察到体检者的血浆氧化低密度脂蛋白(oxLDL)水平与左室室壁厚度呈明显正相关以及oxLDL通过其凝集素样氧化低密度脂蛋白受体（LOX1）介导小鼠心肌肥厚的基础上，拟扩大病例数进行其与心肌重构指标的相关性分析，提出"oxLDL和/或其sLOX1是早期心肌重构的有效诊断指标"学术思想。由于血管紧张素II一型受体（AT1R）激活是心肌重构的关键始动因素，我们在观察到oxLDL/LOX1上调心肌AT1R基础上，拟通过体外体内心脏特异性下调或过表达LOX1或AT1R研究Ox-LDL/LOX1调控AT1R介导心肌重构及核转录因子（NF-κB）是否参与该过程的机制，并在血管紧张素原（ATG-KO）敲除小鼠明确其调控心肌AT1R是否依赖内源性血管紧张素II。本项目的研究突破人们以往对ox-LDL/LOX1主要参与血管损伤的传统认识，拓展其对心肌效应全新认识，为早期心肌重构的诊治提供新的思路。

OxLDL对血管损伤及机制研究比较多，但其在心肌重构中的作用研究甚少。通过该项目的研究，我们观察到体检者的血浆氧化低密度脂蛋白(oxLDL)水平与左室室壁厚度呈明显正相关以及高血压患者血浆的可溶性凝集素样氧化低密度脂蛋白受体（sLOX1）明显升高，提示ox-LDL/LOX1与早期心肌重构有关。我们通过体内体外实验观察到oxLDL通过激活LOX1和AT1受体介导心肌肥厚，并且进一步在血管紧张素原（ATG-KO）敲除小鼠观察到oxLDL致心肌肥厚的作用，提示该效应可不依赖于血管紧张素II(AngII)。进一步在细胞水平和整体水平上阐明ox-LDL可促进LOX1与AT1R结合激活AT1R直接介导心肌肥厚，该过程可不依赖于血管紧张素II，并进一步明确LOX1与AT1R结合的活性区域，即LOX1的266/267位点和AT1R的257位点是这两者受体的结合部位，对于受体激活介导下游心肌肥大效应有关键性的作用。也观察到AT1R的257位点感受机械应力介导心肌肥大的敏感位点，并发现在oxLDL作用下，LOX1和AT1R受体结合，激活AT1R受体,是通过下游Gq蛋白信号通路激活ERK信号，介导心肌肥大反应，而与下游Jak2, Rac1 and RhoA通路无关。本项目的研究有利于人们对ox-LDL/LOX1介导心肌重构方面有全新认识，对于开发LOX1抑制剂或新型AT1受体拮抗剂防治早期心肌重构，保护心功能，延缓心力衰竭的发生发展有积极的意义。