HIF-1α/LincRNA-p21信号通路在心肌梗死后淋巴管新生中的调控作用研究

Myocardial infarction (MI) is a major contributor to mortality and morbidity worldwide. Myocardial edema is one of the most important pathophysiological attributors to MI prognosis, which is caused by the imbalance between microvascular permeability and lymphatic drainage. Recent studies showed that strategies targeting lymphangiogenesis exerted obvious protection from myocardial edema and cardiac dysfunction after MI. However, the mechanisms underlying that remain unclear. In our previous study, we found obvious myocardial edema and lymphangiogenesis and accumulated hypoxia induced factor 1α (HIF-1α) after MI. Moreover, the proliferation and migration was greatly inhibited and the expression of long non-coding RNA-p21 (LincRNA-p21) was reduced after administration of HIF-1α inhibitor to cardiac lymphatic endothelial cells (LECs) subjected to hypoxia. These suggest that HIF-1α/ LincRNA-p21 signaling pathway might be an important regulatory mechanism of lymphangiogenesis after MI. Based on these preliminary data, we will employ mice MI model to fully decribe the dynamic changes of myocardial edema and lymphangiogenesis after MI, make use of cardiac LECs to testify HIF-1α as a key regulator of lymphangiogenesis and LincRNA-p21 expression, and construct cardiac LECs-specific HIF-1α or LincRNA-p21 knockout mice to finally demonstrate the role of HIF-1α/LincRNA-p21 axis in lymphangiogenesis after MI in vivo, which will supply theoratical and experimental foundation for the development of treatment strategies and prognosis improvement of MI.

心肌梗死（MI）是全球性致死致残的主要疾病。心肌水肿作为影响MI预后的重要病生改变，由微血管通透性和淋巴管引流失衡造成。靶向淋巴管新生可减轻MI后心肌水肿，但机制不清。我们前期发现MI后心肌水肿和淋巴管新生增加，缺氧诱导因子1α（HIF-1α）累积；抑制HIF-1α活性后缺氧心脏淋巴管内皮细胞（LECs）增殖和迁移降低、长链非编码RNA-p21（LincRNA-p21）减少。提示HIF-1α/LincRNA-p21是MI后淋巴管新生重要调控机制。基于此，我们将利用小鼠MI模型系统研究MI后心肌水肿和淋巴管新生动态变化，利用心脏LECs证实HIF-1α是淋巴管新生关键调控分子及其对LincRNA-p21的靶向调控作用，并构建心脏LECs特异性HIF-1α和LincRNA-p21敲除小鼠在体阐明HIF-1α/LincRNA-p21轴在MI后淋巴管新生中的作用，为MI治疗和预后改善提供实验依据。

心肌梗死是严重威胁人类健康和生命的重大心血管病。心肌水肿作为心肌梗死后重要病理生理改变，可从多个层面影响心脏功能和预后。淋巴管是组织液引流的重要通道，在心肌梗死后呈现代偿性增生，可部分缓解心肌水肿。如何进一步提升淋巴管引流能力以缓解心肌水肿、进而改善心肌梗死预后成为近年来关注的焦点。本项目通过结扎左冠状动脉前降支构建小鼠心肌梗死模型，发现心肌梗死后组织水肿持续存在、淋巴管新生明显增加。低氧诱导因子-1α（HIF-1α）在梗死心肌淋巴管内皮细胞（LECs）和缺氧LECs中均明显升高，特异性抑制HIF-1α可加重梗死后心肌水肿、减少淋巴管新生，明显抑制LECs增殖和迁移能力。表明HIF-1α是心肌梗死后淋巴管新生的关键调控分子。为进一步发掘HIF-1α的作用机制，我们采用测序技术筛选并验证了基因间长链非编码RNA-p21（LincRNA-p21）是HIF-1α下游调控分子。HIF-1α通过调控LincRNA-p21水平影响LECs增殖和分化，最终影响淋巴管新生。综上所述，本研究明确了HIF-1α在心肌梗死后淋巴管新生中的关键调控作用，阐明了HIF-1α/ LincRNA-p21轴是调控心肌梗死后淋巴管新生的重要通路，有助于加深对心肌梗死后淋巴管新生调控机制的认识、加速以调控机制为切入点的治疗策略的研发，具有重要的科学意义和临床转化价值。