Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.
J Vasc Res. 2021;58(5):311-320. doi: 10.1159/000515177. Epub 2021 Apr 21.
Pathogenesis of cardiovascular diseases begins with endothelial dysfunction. Our previous study has shown that advanced glycation end products (AGE) could inhibit the expression of homeobox A9 (Hoxa9), thereby inducing endothelial dysfunction. Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) has been found to participate in a variety of pathological processes, but reports of its role in endothelial dysfunction are rare.
This study aims to investigate whether LRRFIP1 is involved in AGE-induced endothelial dysfunction through Hoxa9-mediated transcriptional activation.
Chromatin immunoprecipitation was used to detect the transcriptional regulation of Hoxa9 on LRRFIP1 promoters. Human umbilical vein endothelial cells were treated with AGE or pyrrolidinedithiocarbamate (nuclear factor kappa-B [NF-κB] inhibitor). Moreover, changes in apoptosis, proliferation, migration, release of nitric oxide, and angiogenesis were detected.
Hoxa9 promotes LRRFIP1 expression by binding to the -LRRFIP1 promoter. Meanwhile, overexpression of LRRFIP1 inhibited phosphorylation of P65 and elevated expression of Hoxa9. Overexpression of LRRFIP1 or/and Hoxa9 reversed the effects of AGE on HUVEC. AGE-induced inhibition on the expression of LRRFIP1 and Hoxa9 could be reversed by the NF-κB inhibitor.
LRRFIP1 is involved in AGE-induced endothelial dysfunction via being regulated by the NF-κB/Hoxa9 axis.
心血管疾病的发病机制始于血管内皮功能障碍。我们之前的研究表明，晚期糖基化终产物（AGE）可抑制同源盒 A9（Hoxa9）的表达，从而诱导血管内皮功能障碍。富含亮氨酸重复的无翅型整合蛋白 1（LRRFIP1）已被发现参与多种病理过程，但关于其在血管内皮功能障碍中的作用的报道很少。
本研究旨在通过 Hoxa9 介导的转录激活来研究 LRRFIP1 是否参与 AGE 诱导的内皮功能障碍。
采用染色质免疫沉淀法检测 Hoxa9 对 LRRFIP1 启动子的转录调控。用 AGE 或吡咯烷二硫代氨基甲酸盐（核因子 kappa-B [NF-κB] 抑制剂）处理人脐静脉内皮细胞。此外，还检测了细胞凋亡、增殖、迁移、一氧化氮释放和血管生成的变化。
Hoxa9 通过与-LRRFIP1 启动子结合促进 LRRFIP1 的表达。同时，LRRFIP1 的过表达抑制了 P65 的磷酸化，并上调了 Hoxa9 的表达。LRRFIP1 的过表达或/和 Hoxa9 的过表达逆转了 AGE 对 HUVEC 的作用。NF-κB 抑制剂可逆转 AGE 诱导的 LRRFIP1 和 Hoxa9 表达抑制。
LRRFIP1 通过 NF-κB/Hoxa9 轴参与 AGE 诱导的内皮功能障碍。
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