As the most common cardiovascular disease, atherosclerosis (AS), is a leading cause of high mortality in patients with chronic renal failure. Rab27a has been reported to regulate the progression of cardiovascular and renal diseases. Nevertheless, little studies investigated the role and mechanism of Rab27a in uremic-accelerated AS (UAAS). An animal model of UAAS was established in apolipoprotein E knockout (apoE^−/−) mice using 5/6 nephrectomy (NX). We conducted in vitro and in vivo functional experiments to explore the role of Rab27a in UAAS, including the presence of oxidized low-density lipoprotein (ox-LDL). Rab27a expression was upregulated in the plaque tissues of NX apoE^−/− mice. The knockout of Rab27a (Rab27a^−/−) reduced AS-induced artery injury, as manifested by the reductions of plaque area, collagen deposition, inflammation and lipid droplet. Besides, cholesterol efflux was increased, while the expression of lipid metabolism-related proteins and the secretions of pro-inflammatory factors were decreased in ox-LDL-induced NX Rab27a^−/− apoE^−/− mice group. Further, Rab27a deletion inhibited the activation of nuclear factor κB (NF-κB) pathway. In conclusion, our study indicated that Rab27a deficiency attenuated foam cell formation and macrophage inflammation, depending on the NF-κB pathway activation, to inhibit AS progression in uremic apoE^−/− mice. This finding may provide a new targeting strategy for UAAS therapy.

作为最常见的心血管疾病，动脉粥样硬化（AS）是慢性肾功能衰竭患者高死亡率的主要原因。据报道，Rab27a可以调节心血管和肾脏疾病的进展。然而，很少有研究探讨Rab27a在尿毒症加速 AS（UAAS）中的作用和机制。采用 5/6 肾切除术 (NX)在载脂蛋白 E 敲除 ( apoE ^{− /−} ) 小鼠中建立 UAAS 动物模型。我们进行了体外和体内功能实验来探索Rab27a在 UAAS 中的作用，包括氧化低密度脂蛋白 (ox-LDL) 的存在。NX 斑块组织中Rab27a表达上调apoE ^{− /−}小鼠。Rab27a ( Rab27a ^−/− )的敲除减少了 AS 引起的动脉损伤，表现为斑块面积、胶原蛋白沉积、炎症和脂滴的减少。此外，ox-LDL诱导的NX Rab27a ^−/− apoE ^{− /−} 小鼠组胆固醇流出增加，脂质代谢相关蛋白表达和促炎因子分泌减少。此外，Rab27a缺失抑制核因子 κB (NF-κB) 通路的激活。总之，我们的研究表明Rab27a缺乏可减弱泡沫细胞的形成和巨噬细胞炎症，这取决于 NF-κB 通路的激活，从而抑制尿毒症apoE ^−/−小鼠的 AS 进展。这一发现可能为UAAS治疗提供新的靶向策略。