SR-A1介导的巨噬细胞活性改变在肥胖诱导的高血压中的作用及其机制研究

A large number of epidemiological studies have shown that an increase in obesity is one of the major causes of cardiovascular morbidity and mortality. A series of studies have shown that the interaction between the perivascular adipose tissue (PVAT) and the vascular may be an important mechanism for maintaining vascular homeostasis. Therefore, study of PVAT dysfunction is the key to elucidating the causal relationship between obesity and hypertension. Macrophages are the most abundant immune cells in adipose tissue, and macrophage activity changes play an important role in PVAT dysfunction. Class A1 scavenger receptor (SR-A1) is one of pattern recognition receptors that are expressed primarily on the surface of macrophages and are involved in regulating many of the biological functions of macrophages, including inflammatory cytokines, cell proliferation and lipid accumulation. The project intends to further explore the molecular mechanism of SR-A1 regulation of macrophage activity as a clue, in-depth study of macrophages, adipocytes and vascular endothelial cells between the interactions and found that the new adipokines. It is of great significance to elucidate the pathogenesis of obesity and to fully understand the role of macrophages in obesity-related diseases.

大量的流行病学调查结果证明，肥胖人群的增加是造成心血管病发病率和死亡率上升的一个主要原因。肥胖时管周脂肪组织（PVAT）与血管壁之间的交互作用可能是维持血管稳态的重要机制。因此，系统性地研究PVAT功能异常是阐明肥胖和高血压之间因果关系的关键所在。巨噬细胞是脂肪组织中含量最丰富的免疫细胞，巨噬细胞活性的改变在PVAT功能异常中发挥重要的作用。A1类清道夫受体（SR-A1）是一类重要的模式识别受体，主要表达于巨噬细胞膜表面，参与调控巨噬细胞的许多生物学功能，包括炎症因子分泌、细胞粘附、增殖以及脂质积聚等。本项目拟进一步以发掘SR-A1调控巨噬细胞活性的分子机制为线索，深入研究巨噬细胞、脂肪细胞和血管内皮细胞之间的交互作用，发现新的脂肪因子，对于阐明肥胖引起高血压的发病机制，全面认识巨噬细胞在肥胖相关性疾病中的作用具有重要的意义。

已知A1类清道夫受体（SR-A1）是一类重要的模式识别受体主要表达于巨噬细胞膜表面，能够识别范围广泛的多聚阴离子配体，参与调控巨噬细胞的许多生物学功能，包括炎症因子分泌、细胞粘附、细胞增殖以及脂质积聚等。本项目开展的肥胖相关性高血压研究，以巨噬细胞SR-A1作为主线，通过探讨PVAT影响血管病变的炎性机制，着力阐明血管稳态及重构过程中巨噬细胞的炎性调控网络，为深入认识和解决血管相关重大疾病提供理论依据，为发现新的疾病干预靶标奠定基础。我们的研究结果提示，巨噬细胞SR-A1-VEGF-B反应轴对肥胖性高血压具有重要的调节作用。德国缅因茨大学Wenzel教授在同期杂志发表述评，认为SR-A1或者表达SR-A1的巨噬细胞可以作为保护肥胖引起的内皮功能障碍的重要靶点。