Haplo-insufficiency of Profilin1 in vascular endothelial cells is beneficial but not sufficient to confer protection against experimentally induced atherosclerosis.
Haplo-insufficiency of Profilin1 in vascular endothelial cells is beneficial but not sufficient to confer protection against experimentally induced atherosclerosis.
复制标题
血管内皮细胞中Profilin1的单倍体不足是有益的，但不足以提供针对实验诱导的动脉粥样硬化的保护。
DOI：
10.1101/2023.12.06.570450
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Roy,Partha
中科院分区：
文献类型：
--
作者：
Allen-Gondringer,Abigail;Gau,David;Dutta,Partha;Roy,Partha
肌动蛋白细胞骨架在动脉粥样硬化的各个方面起着重要作用，动脉粥样硬化是缺血性心脏病的关键驱动因素。肌动蛋白结合蛋白Profilin1（Pfn1）在人类疾病的动脉粥样硬化斑块中过表达，并且当Pfn1在所有细胞类型中部分耗尽时，在体内赋予动脉粥样硬化保护作用。本研究探讨了动脉粥样硬化发展中内皮细胞（EC）特异性Pfn1表达部分缺失的影响。我们使用了在EC中Pfn1基因条件性杂合敲除的小鼠，通过PCSK 9基因递送结合高胆固醇饮食消耗肝脏LDL受体诱导动脉粥样硬化。我们的研究表明，部分去除EC Pfn1具有某些有益作用，其特征在于抑制选择的促动脉粥样硬化细胞因子（CXCL10和IL7），同时降低细胞毒性T细胞丰度，但不足以降低高脂血症并赋予体内动脉粥样硬化保护作用。根据这些发现，我们得出结论，全球Pfn1单倍型不足所赋予的动脉粥样硬化保护表型需要与动脉粥样硬化进展相关的其他细胞类型的贡献。
Actin cytoskeleton plays an important role in various aspects of atherosclerosis, a key driver of ischemic heart disease. Actin‐binding protein Profilin1 (Pfn1) is overexpressed in atherosclerotic plaques in human disease, and Pfn1, when partially depleted globally in all cell types, confers atheroprotectionin vivo. This study investigates the impact of endothelial cell (EC)‐specific partial loss of Pfn1 expression in atherosclerosis development. We utilized mice engineered for conditional heterozygous knockout of the Pfn1 gene in ECs, with atherosclerosis induced by depletion of hepatic LDL receptor by gene delivery of PCSK9 combined with high‐cholesterol diet. Our studies show that partial depletion of EC Pfn1 has certain beneficial effects marked by dampening of select pro‐atherogenic cytokines (CXCL10 and IL7) with concomitant reduction in cytotoxic T cell abundance but is not sufficient to reduce hyperlipidemia and confer atheroprotectionin vivo. In light of these findings, we conclude that atheroprotective phenotype conferred by global Pfn1 haplo‐insufficiency requires contributions of additional cell types that are relevant for atherosclerosis progression.