C型凝集素受体Dectin-1调节NLRP3小体活性及巨噬细胞炎症反应介导肺动脉高压相关右心室重构的机制研究

Right ventricular remodeling and dysfunction is a key prognosis effector of pulmonary hypertension. Inflammatory response modulates the degree of PAH and PAH induced right ventricular remodeling and dysfunction. Our preliminary studies suggested that receptor Dectin-1 was up-regulated in right ventricular of PAH mouse, Dectin-1 deficiency mouse exhibited attenuated cardiac hypertrophy and fibrosis, accompanied with decrease IL-1β and IL-18, which is the activationproduction of inflammasome. However, the exact mechanism of Dectin-1 on Right ventricular remodeling is still unknown. In this project, we hypothesis that cardiomyocyte injured by PAH could release the activator of Dectin-1, which further promote the activation of Inflammasome to increase inflammatory response of the right ventricular, Dectin-1 promotes right ventricular remodeling and dysfunction after PAH. To verify this hypothesis, we will use Dectin-1-/- mouse and Nlrp3-/- mouse in vivo, bone marrow transplantation, RNA-seq and cells co-culture in vitro to reveal the molecular mechanism of Dectin-1 and inflammasome in right ventricular remodeling and dysfunction after PAH. Our research will provide the novel ideals and experimental basis for the prognosisimprovement of PAH therapy.

右心重塑、衰竭是肺动脉高压（PAH）预后的关键决定因素，炎症反应影响PAH及其导致的右心重塑和衰竭的程度。课题组前期通过转录组分析发现Dectin-1在PAH小鼠右心室表达显著增加，Dectin-1敲除减轻右室心肌肥厚和纤维化程度，同时炎症小体活化产物IL-1β和IL-18表达减少。但Dectin-1在PAH致右室重塑和心力衰竭中的作用机制尚不清楚。为了验证本研究的科学假说“PAH损伤右心室心肌细胞释放可活化Dectin-1的配体，激Dectin-1依赖的炎症小体的形成，促进右心室炎症反应，加剧心室重构和心力衰竭”，拟使用Dectin-1和NLRP3敲除小鼠制作PAH致右室重塑模型，结合体外细胞共培养、骨髓移植等方法重点明确PAH激活心脏Dectin-1的分子机制，明确Dectin-1依赖的炎症小体活化对右心室重塑和心力衰竭的作用机制，从而为提高PAH治疗的预后提供新思路。

肺动脉高压（Pulmonary artery hypertension）是一组由多种原因引起的、进展迅速、预后极差的疾病。肺动脉高压可导致右心室后负荷增加、右心室肥厚、右心室衰竭。Clec7a 编码蛋白 Dectin-1，是穿膜 C 型凝集素受体家族的一员，主要表达在单核巨噬细胞以及其他骨髓源单核细胞系来源的细胞表面。在先天免疫中发挥重要作用。其可能参与了肺动脉高压导致的右心室重构过程。本研究通过体内体外实验研究了肥大心肌细胞中以及肺动脉高压模型右心室组织中Dectin1的表达。结果发现（1）采用血管紧张素II刺激大鼠H9C2心肌细胞，造成心肌细胞肥大后发现，肥大心肌细胞中Dectin1的表达水平与未加血管紧张素的对照组相比显著升高。这提示Dectin1与心肌肥大有一定的相关性。（2）采用Sugen 联合缺氧建立大鼠肺动脉高压模型，其右心室组织中Dectin1的表达与正常对照组相比明显升高。（3）腺相关病毒AAV9敲低心脏组织中的Dectin1基因后建立大鼠肺动脉高压模型，右心室肥厚指数有下降趋势，右心室纤维化减轻。且右心室组织中心肌肥厚指标BNP的mRNA表达减少；心肌损伤指标β-MHC的mRNA表达减少。这些研究结果表明Dectin1参与肺动脉高压导致的右心室重构过程，相应的抑制Dectin1会一定程度的减轻心室重构。因此，Dectin1可以作为肺动脉高压致使右心重构 过程中的一个重要干预靶点。

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