盐皮质激素受体调控内膜新生和血管重构

Inflammation and oxidative stress play important roles in the process of neointima formation and vascular remodeling. Macrophages are one of the critical players. However, it is not completely clear how to effectively regulate the function of these cells under these pathological conditions. Recent data and our preliminary results demonstrated that blockade of mineralocorticoid receptor (MR) could protect cardiovascular system by regulating the function of macrophages as well as inflammation and oxidative stress. Therefore, we hypothesize that blockade of MR, particularly MR in macrophages, inhibits neointima formation and vascular remodeling by decreasing inflammation and oxidative stress to reduce proliferation and migration of vascular smooth muscle cells and fibroblasts. We will utilize MR antagonist and cell type-specific knockout (MRKO) mouse models, in combination with mouse model of arterial injury, to study how MR blockade regulates inflammation and oxidative stress and therefore affects neointima formation and vascular remodeling. We will also use cell culture to explore the signaling pathways and molecular mechanisms how MRKO affects inflammation and oxidative stress in macrophages. We will further study how MRKO macrophages affect inflammation, oxidative stress, proliferation, and migration of vascular smooth muscle cells and fibroblasts using co-culture system. The outcome of these studies may identify myeloid MR as a therapeutic target, providing new strategies for intervention of neointima formation and vascular remodeling in a cell type-specific manner.

炎症和氧化应激是内膜新生和血管重构过程中的重要机制，其中巨噬细胞发挥关键作用。然而如何在这些病理过程中有效地调控巨噬细胞的功能尚不完全清楚。近期数据和前期结果表明盐皮质激素受体（MR）阻断可以调控巨噬细胞的功能以及炎症和氧化应激，从而保护心血管系统。因此我们推测MR阻断，尤其是巨噬细胞MR阻断，通过降低炎症和氧化应激，抑制血管平滑肌细胞和成纤维细胞的增殖和迁移，从而抑制内膜新生和血管重构。将利用MR拮抗剂和细胞特异性MR敲除（MRKO）小鼠，结合动脉损伤模型，研究MR阻断如何调控炎症和氧化应激，从而影响内膜新生和血管重构；利用细胞培养探索MRKO影响巨噬细胞炎症和氧化应激的信号通路和分子调控机制；进而利用共培养，研究MRKO巨噬细胞如何影响血管平滑肌细胞和成纤维细胞的炎症、氧化应激、增殖和迁移。研究结果有望把巨噬细胞MR确定为作用靶点，为干预内膜新生和血管重构提供新的药物靶向证据。

动脉粥样硬化（AS）和经皮冠状动脉介入治疗后再狭窄都是尚未完全解决的重要临床问题。虽然实验数据表明盐皮质激素受体（MR）是治疗AS和再狭窄的潜在作用靶点，但临床证据尚有争议，而且细胞和分子机制尚不明确。在这项研究中，我们探讨了巨噬细胞MR在AS发生发展以及血管损伤后内膜新生过程中的功能以及细胞和分子机制。在AS方面，我们发现：1）巨噬细胞MR敲除（MMRKO）显著降低高胆固醇饮食诱导的LDLRKO小鼠的AS斑块；2）在ApoEKO小鼠灌注血管紧张素II的模型中，MMRKO也显著抑制AS斑块；3）MMRKO降低斑块内坏死和巨噬细胞聚集、增加胶原覆盖；4）MMRKO抑制泡沫细胞的形成、上调胆固醇外排相关基因的表达、并增加有效的巨噬细胞胞葬。在内膜新生方面，我们发现：1）MMRKO抑制动脉损伤引起的血管内膜新生以及血管炎症；2）MMRKO抑制巨噬细胞迁移与增殖；3）MMRKO巨噬细胞条件培养基诱导的血管平滑肌细胞迁移、增殖和炎性基因表达均减少；4）MMRKO抑制巨噬细胞炎症反应并通过SGK1抑制AP1和NF-κB信号通路。总之，这些研究结果为靶向巨噬细胞MR及其相关信号通路从而治疗AS和再狭窄提供了理论基础和新的思路。