前列腺素D2在血管损伤反应中作用及其转化研究

Vascular injury leads to perivascular inflammatory cell infiltration and neointimal hyperplasia. Prostaglandin D2 （PGD2）is believed to mediate active inflammatory resolution, its receptors-DP1 and DP2, are mainly expressed in vasculature and inflammatory cells, respectively. Naicin, also known as vitamin B3, is old lipid lowering drug, which could cause facial flashing by releasing PGD2 in vivo. However, whether PGD2 and niacin is involved in injury induced vascular remodeling remains poorly understood. We observed deletion of either DP1 or DP2 significantly reduced wire injury-induced neointimal formation in mice; autophagy related genes (Atgs) is upregulated in femoral artery tissues followed by wire injury; PGD2 could suppress PDGF-BB triggered autophagy in primary cultured VSMCs and restrain VSMC proliferation. In this proposal, we will examine if PGD2/DP1 axis regulates vascular remodeling through modulation of autophagy, and identify the LC3- regulated miRNAs which govern VSMC proliferation. At same time, we will screen the differentially secreted cytokines from DP2 KO and WT T cells; and clarify how these cytokines regulate VSMC migration in T-cell/VSMC co-culture system. Ultimately, we will determine if niacin play any role in maintaining vascular homeostasis after injury through stimulation of PGD2 release. This study may bring about discovery of novel drug target for coronary artery disease and new aspect niacin for treatment of cardiovascular diseases.

血管损伤引起炎症细胞浸润和内膜增生等血管重塑反应。前列腺素D2（PGD2)介导了局部炎症的主动消退，其受体DP1和DP2主要分别在血管组织和炎症细胞中有高表达；烟酸一种降低胆固醇的维生素B类药，可以促进组织细胞释放PGD2，但是PGD2和烟酸对血管重塑作用仍不清楚。我们发现分别敲除 DP1和DP2受体，血管损伤后内膜增生加重；深度测序表明血管损伤后自噬相关基因表达增高，PGD2处理明显抑制VSMC自噬现象和细胞增长。我们将研究PGD2/DP1是否调节血管损伤后VSMC自噬和内膜增生，组学手段鉴定自噬基因LC3调控与VSMC生长相关的miRNA；同时通过蛋白芯片分析比较DP2敲除与对照T细胞分泌的差异细胞因子，共培养分析DP2 敲除T细胞来源的细胞因子如何促进VSMC迁移；最后，分析烟酸是否通过促进释放PGD2来维持血管损伤后稳态。这研究有望发现冠心病治疗的新靶点和烟酸的抗心血管病新机制。

血管损伤反应包括血管炎症和血管病理性重构，前列腺素D2(PGD2)是一种重要的炎性介质，在病理性血管重构作用不清楚。本课题通过多种分子生物学学和组学手段，发现PGD2可以通过DP1受体促进M2极化介导心血管炎症消退；DP1受体抑制损伤导致血管平滑肌细胞自噬从而抑制损伤后血管内膜新生；PGD2受体CRTH2表达在肺动脉高压病人T细胞中升高，并促进低氧导致肺血管重构；同时，我们也发现PGE2通过激活肝细胞EP3受体促进胆固醇降解，进而抑制高脂诱导动脉粥样硬化；EP3受体介导内皮细胞出芽和血管新生；EP3促进低氧诱导的肺动脉重构。烟酸促进PGD2释放，并有利于炎症的消退。这些结果为临床上非激素类抗炎药（NSAID）与烟酸的正确使用提供理论指导，并有望找到新的心血管疾病预防与治疗靶点。