心力衰竭IL-33/sST2变化调控VSMC线粒体自噬和生成促进动脉粥样硬化斑块不稳定机制研究

Acute coronary events (ACE), which are secondary to unstable coronary atherosclerotic plaque, are the most important causes for death in patients with chronic heart failure (CHF) due to ischemia. Soluble ST2 predicts ACE only in patients with high levels of IL-33, which stabilizes atherosclerotic plaque. Impaired mitophagy and mitochondriogenesis in vascular smooth muscle cell (VSMC) are the key alterations leading to unstable plaque formation. IL-33 increases mitochondria both in function and number aspects. Our preliminary experiment also revealed that it promoted mitophagy and mitochondriogenesis. Our previous study demonstrated that IL-33 activated STAT3, as a transcriptional factor, and ATG5 is the downstream target gene of STAT3. Besides, IL-33 up-regulated FGF-21 that enhanced PGC-1α translation, which is the key protein in regulating mitochondriogenesis. Therefore, we raised the following scientific issues: (1) In CHF patients, does sST2 unstabilized atherosclerotic plaque via inhibition the increased effects on mitophagy and mitochondriogenesis of IL-33? (2) Does IL-33 respectively accelerate mitophagy and mitochondriogenesis in VSMC via STAT3/ATG5 and FGF-21/PGC-1α and thus stabilizing atherosclerotic plaque? (3) Does serum levels of IL-33 and sST2 predict ACE in CHF patients? To solve these issues, we plan to up- or down- regulate key factors in these pathways and elucidate the effects of IL-33/sST2 on plaque stability in CHF status, and evaluate the value of IL-33/sST2 in predicting ACE among CHF patients. Our project will provide more clues for ACE alarming in CHF patients.

不稳定斑块导致急性冠脉事件（ACE）是伴有冠心病的心力衰竭患者重要死因。sST2可预测ACE但仅限于高IL33人群，而IL33能稳定斑块。VSMC线粒体自噬和生成不足是不稳定斑块形成的关键。IL33上调线粒体功能和数量并促进VSMC线粒体自噬和生成。它激活STAT3，而ATG5是STAT3下游基因；它上调FGF21，而FGF21又增强PGC1α翻译。因此，本项目提出以下关键科学问题：1. 心力衰竭中sST2是否通过抑制IL33负调控线粒体自噬和生成并促使斑块不稳定；2. IL33是否分别通过STAT3/ATG5和FGF21/PGC1α促进线粒体自噬和生成而稳定斑块；3. 血清IL33/sST2能否帮助预测心衰患者ACE发生。围绕科学问题，项目拟上调/下调其中关键分子，阐明IL33/sST2对心衰斑块稳定性影响和机制并揭示IL-33/sST2预测心衰患者ACE价值，为心衰ACE预警提供思路。

冠状动脉粥样硬化性心脏病及其并发症连续5年占据中国居民死亡原因第二位，也是心力衰竭最重要的病因。在伴有冠心病的心力衰竭患者中，高达50%以上的死亡由急性冠脉事件直接或间接造成。而急性冠脉事件的主要发病基础是冠状动脉不稳定的粥样硬化斑块。因此，本项目立足于冠状动脉粥样硬化不稳定斑块及心力衰竭两大疾病模型，探讨在其过程中可能有重要作用的分子靶点及重要机制。该项目不仅发现了血管平滑肌细胞中的lncRNA PART1, FTO等在动脉粥样硬化不稳定斑块进展过程中起重要作用；另一方面，项目负责人也发现了该项目的重要分子IL-33在小鼠糖尿病心肌病模型中的治疗作用以及该项目的重要机制线粒体自噬在心衰模型中心肌成纤维细胞活化中的重要作用。总体上，该项目的主要研究内容为靶向治疗冠心病提供了一定程度的基础实验的证据，也为以后冠心病的进一步的研究奠定了较好的基础。