1 Vascular Biology Program Centre for the Endothelium Centenary Institute The University of Sydney Newtown Australia.
2 Immune Imaging Program, Centenary Institute The University of Sydney Newtown Australia.
J Am Heart Assoc. 2019 Jan 22;8(2):e010057. doi: 10.1161/JAHA.118.010057.
Background Vascular endothelial cell (EC) alignment in the direction of flow is an adaptive response that protects against aortic diseases, such as atherosclerosis. The Rho GTP ases are known to regulate this alignment. Herein, we analyze the effect of ARHGAP 18 on the regulation of EC alignment and examine the effect of ARHGAP 18 deficiency on the development of atherosclerosis in mice. Methods and Results We used in vitro analysis of ECs under flow conditions together with apolipoprotein E Arhgap 18 double-mutant mice to study the function of ARHGAP 18 in a high-fat diet-induced model of atherosclerosis. Depletion of ARHGAP 18 inhibited the alignment of ECs in the direction of flow and promoted inflammatory phenotype, as evidenced by disrupted junctions and increased expression of nuclear factor-κB and intercellular adhesion molecule-1 and decreased endothelial nitric oxide synthase. Mice with double deletion in ARHGAP 18 and apolipoprotein E and fed a high-fat diet show early onset of atherosclerosis, with lesions developing in atheroprotective regions. Conclusions ARHGAP 18 is a protective gene that maintains EC alignments in the direction of flow. Deletion of ARHGAP 18 led to loss of EC ability to align and promoted atherosclerosis development.
背景 血管内皮细胞（EC）沿血流方向的排列是一种适应性反应，可预防主动脉疾病，如动脉粥样硬化。已知 Rho GTPases 可调节这种排列。在此，我们分析了 ARHGAP 18 对 EC 排列调节的影响，并研究了 ARHGAP 18 缺乏对小鼠动脉粥样硬化发展的影响。
方法和结果 我们使用了体外分析在流动条件下的 ECs 以及载脂蛋白 E Arhgap 18 双突变小鼠，以研究 ARHGAP 18 在高脂肪饮食诱导的动脉粥样硬化模型中的功能。ARHGAP 18 的耗竭抑制了 EC 沿血流方向的排列，并促进了炎症表型，表现为连接中断，核因子-κB 和细胞间黏附分子-1 的表达增加，内皮型一氧化氮合酶减少。载脂蛋白 E 和高脂肪饮食喂养的 ARHGAP 18 双缺失小鼠出现动脉粥样硬化的早期发病，病变发生在抗动脉粥样硬化区域。
结论 ARHGAP 18 是一种保护性基因，可维持 EC 沿血流方向的排列。ARHGAP 18 的缺失导致 EC 失去排列能力，并促进动脉粥样硬化的发展。
