高血压是引起心脑血管疾病的主要危险因素。血管巨噬细胞极化是导致高血压的重要机制。申请人既往发现免疫蛋白酶体亚基LMP7是调控蛋白质降解和心肌重构的新途径，但在高血压中的作用不清楚。前期发现AngII灌注显著升高血管LMP7水平。LMP7敲除明显抑制AngII诱导的高血压、血管重构、M1型巨噬细胞极化及炎症反应，并在LMP7敲除骨髓移植小鼠中得到验证。为此，我们推测LMP7可能通过调节巨噬细胞向M1型极化促进高血压。本项目拟应用AngII和DOCA-salt诱导的高血压模型，在基因敲除、骨髓移植和抑制剂处理的小鼠及细胞共培养体系中，阐明AngII升高LMP7表达的分子机制；明确LMP7调节血压升高、血管重构和功能异常的病理机制；明确LMP7通过SOCS3/STAT1和IκBα/NF-κB通路调节M1/M2型巨噬细胞极化的分子机制；为阐明LMP7调控高血压的机制及筛选治疗新靶点提供实验依据。

Hypertension is a major risk factor for cardiovascular and cerebrovascular diseases. Vascular macrophage polarization is an important mechanism that causing hypertension. Our previous studies have confirmed that immunoproteasome catalytic subunit LMP7 is a new pathway in regulating protein degradation and myocardial remodeling. The applicant's recent results indicate that angiotensin II (Ang II) infusion can significantly upregulate LMP7 expression levels and chymotrypsin-like activity in blood vessels. Conversely, knockout of LMP7 can significantly inhibit Ang II-induced elevation of blood pressure, vascular remodeling, M1 macrophage polarization and inflammation. These preventive effects were confirmed in wild-type mice transplanted with LMP7-deficient bone marrow cells. Therefore, we speculate that LMP7 may promote hypertension by regulating the polarization of macrophages towards M1. By using Ang II perfusion and DOCA-salt-induced hypertensive mouse models in gene knockout mice, bone marrow transplantation chimera mice, inhibitor-treated mice, and in vitro cell co-cultures, this project aims to clarify the role of Ang II in increasing LMP7 expression and underlying molecular mechanism; explore the pathophysiological mechanism of LMP7 in regulating blood pressure elevation, vascular remodeling and diastolic dysfunction; identify the molecular mechanism of LMP7 regulating M1 / M2 macrophage polarization through SOCS3 / STAT1 and IκBα / NF-kB pathways; and finally our results will provide scientific evidence for clarifying the he mechanism of LMP7 in regulating hypertension and screening the new therapeutic targets.