NDUFA13介导的电子泄漏调控NF-KB活性保护LPS心肌损伤作用机制的研究

Cardiac dysfunction caused by endotoxemia is one of the important causes of systemic shock. Myocardial injury can lead to loss of functional myocardium, decreased ejection fraction, leading to heart failure.So how to reduce the direct effect of myocardial toxicity substances and excessive oxidative stress is the primary task. We reduced acute myocardial injury following endotoxin stimulation by down regulating NDUFA13 expression in the myocardium. In combination with previous work, we think that the electrical shunt may be the mechanism of resistance to LPS-induced myocardial injury. This project intends to use myocardial injury model, oxygen consumption detection, electron spin resonance, high performance liquid chromatography and other technologies. By studying the changes of myocardial anti-apoptotic capacity, myocardial metabolism and the type of free radicals, to investigate the changes of myocardial signaling pathways associated with LPS after NDUFA13 downregulation. We focus on the electronic impact of IκB-NFκB dissociation activation and STAT3, NFκB co-transcriptional regulation, to further study the mechanism of NDUFA13 downregulation in the protection of acute myocardial injury and provide new possibilities for myocardial protection therapy.

内毒素血症致心功能损害是全身休克的重要病因之一，心肌损伤致使功能心肌丢失射血分数减低最终导致心衰产生，减少心肌毒性物质直接作用和过度氧化应激是缓解心肌急性损伤的首要任务。前期通过下调心肌NDUFA13表达量，我们减少了心肌组织在内毒素刺激下的急性坏死。结合先前工作NDUFA13下调分流堆积电子可减少心肌细胞的缺血再灌注损伤，我们认为电子分流可能是抵抗LPS诱导的心肌急性损伤信号通路下调的机制和源头。本项目拟应用模式生物心肌损伤模型、氧耗检测、电子自旋共振、高效液相色谱等技术通过研究心肌抵抗凋亡能力的变化，心肌代谢水平和自由基类型分布的改变，探讨NDUFA13下调对LPS心肌损伤相关信号通路的改变和具体机制，重点关注泄漏电子影响的IκB-NFκB解离激活和STAT3、NFκB的协同转录调控，以进一步补完NDUFA13下调对心肌急性损.伤保护作用的机制，为心肌保护治疗提供新的可能性。

心肌细胞因其为心脏连续供能而具有丰富的线粒体含量，而在各类心肌氧化应激损伤过程中却成为了高能量电子和活性氧物质的重要来源，是造成心肌细胞丢失的最主要元凶之一。我们既往在国际上发现了NDUFA13因其特殊的位置和结构，使其下调可以明显减少心肌细胞的缺血再灌注损伤。但同时期检测到的非线粒体源性凋亡信号通路下调的机制依旧不明。本项目通过模式生物结合病毒转染等技术证明了内毒素血证时NDUFA13泄漏电子可通过NFκB活性程度变化及转位抑制心肌细胞凋亡，并通过氧耗检测、电子自旋共振、以进一步从高能自由电子组成及含量水平变化以减少氧化应激损伤，同时研究内毒素诱导在体心肌调亡过程中周围成纤维细胞及巨噬细胞调控作用，完善NDUFA13下调对心肌损伤保护作用的机制，为心肌保护治疗提出新的领域。