Conditional deletion of Ccl2 in smooth muscle cells does not reduce early atherosclerosis in mice

IF 1.4 Q3 PERIPHERAL VASCULAR DISEASE
Stine Gunnersen , Jeong Tangkjær Shim , Fan Liu , Uwe J.F. Tietge , Charlotte Brandt Sørensen , Jacob Fog Bentzon
{"title":"Conditional deletion of Ccl2 in smooth muscle cells does not reduce early atherosclerosis in mice","authors":"Stine Gunnersen ,&nbsp;Jeong Tangkjær Shim ,&nbsp;Fan Liu ,&nbsp;Uwe J.F. Tietge ,&nbsp;Charlotte Brandt Sørensen ,&nbsp;Jacob Fog Bentzon","doi":"10.1016/j.athplu.2023.12.004","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and aims</h3><p>C–C motif chemokine ligand 2 (CCL2) is a pro-inflammatory chemokine important for monocyte recruitment to the arterial wall and atherosclerotic plaques. Global knockout of <em>Ccl2</em> reduces plaque formation and macrophage content in mice, but the importance of different plaque cell types in mediating this effect has not been resolved. Smooth muscle cells (SMCs) can adopt a potentially pro-inflammatory function with expression of CCL2. The present study aimed to test the hypothesis that SMC-secreted CCL2 is involved in early atherogenesis in mice.</p></div><div><h3>Methods</h3><p>SMC-restricted Cre recombinase was activated at 6 weeks of age in mice with homozygous floxed or wildtype <em>Ccl2</em> alleles. Separate experiments in mice lacking the Cre recombinase transgene were conducted to control for genetic background effects. Hypercholesterolemia and atherosclerosis were induced by a tail vein injection of recombinant adeno-associated virus (rAAV) encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and a high-fat diet for 12 weeks.</p></div><div><h3>Results</h3><p>Unexpectedly, mice with SMC-specific <em>Ccl2</em> deletion developed higher levels of plasma cholesterol and larger atherosclerotic plaques with more macrophages compared with wild-type littermates. When total cholesterol levels were incorporated into the statistical analysis, none of the effects on plaque development between groups remained significant. Importantly, changes in plasma cholesterol and atherosclerosis remained in mice lacking Cre recombinase indicating that they were not caused by SMC-specific CCL2 deletion but by effects of the floxed allele or passenger genes.</p></div><div><h3>Conclusions</h3><p>SMC-specific deficiency of <em>Ccl2</em> does not significantly affect early plaque development in hypercholesterolemic mice.</p></div>","PeriodicalId":72324,"journal":{"name":"Atherosclerosis plus","volume":null,"pages":null},"PeriodicalIF":1.4000,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667089523000512/pdfft?md5=7d5a4c8de844186df973dac21adc4df3&pid=1-s2.0-S2667089523000512-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Atherosclerosis plus","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2667089523000512","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
引用次数: 0

Abstract

Background and aims

C–C motif chemokine ligand 2 (CCL2) is a pro-inflammatory chemokine important for monocyte recruitment to the arterial wall and atherosclerotic plaques. Global knockout of Ccl2 reduces plaque formation and macrophage content in mice, but the importance of different plaque cell types in mediating this effect has not been resolved. Smooth muscle cells (SMCs) can adopt a potentially pro-inflammatory function with expression of CCL2. The present study aimed to test the hypothesis that SMC-secreted CCL2 is involved in early atherogenesis in mice.

Methods

SMC-restricted Cre recombinase was activated at 6 weeks of age in mice with homozygous floxed or wildtype Ccl2 alleles. Separate experiments in mice lacking the Cre recombinase transgene were conducted to control for genetic background effects. Hypercholesterolemia and atherosclerosis were induced by a tail vein injection of recombinant adeno-associated virus (rAAV) encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and a high-fat diet for 12 weeks.

Results

Unexpectedly, mice with SMC-specific Ccl2 deletion developed higher levels of plasma cholesterol and larger atherosclerotic plaques with more macrophages compared with wild-type littermates. When total cholesterol levels were incorporated into the statistical analysis, none of the effects on plaque development between groups remained significant. Importantly, changes in plasma cholesterol and atherosclerosis remained in mice lacking Cre recombinase indicating that they were not caused by SMC-specific CCL2 deletion but by effects of the floxed allele or passenger genes.

Conclusions

SMC-specific deficiency of Ccl2 does not significantly affect early plaque development in hypercholesterolemic mice.

平滑肌细胞中 Ccl2 的条件性缺失不会减轻小鼠的早期动脉粥样硬化
背景和目的C-C motif趋化因子配体2(CCL2)是一种促炎性趋化因子,对单核细胞招募到动脉壁和动脉粥样硬化斑块非常重要。全面敲除 Ccl2 可减少小鼠斑块的形成和巨噬细胞的含量,但不同斑块细胞类型在介导这种效应方面的重要性尚未得到解决。平滑肌细胞(SMC)可通过表达 CCL2 发挥潜在的促炎功能。本研究旨在验证 SMC 分泌的 CCL2 参与小鼠早期动脉粥样硬化发生的假设。方法在 6 周龄时,激活同卵或野生型 Ccl2 等位基因小鼠的 SMC 限制性 Cre 重组酶。在缺乏 Cre 重组酶转基因的小鼠中分别进行了实验,以控制遗传背景的影响。高胆固醇血症和动脉粥样硬化是通过尾静脉注射重组腺相关病毒(rAAV)和高脂肪饮食诱导的。结果出乎意料的是,与野生型小鼠相比,SMC特异性Ccl2缺失的小鼠血浆胆固醇水平更高,动脉粥样硬化斑块更大,巨噬细胞更多。将总胆固醇水平纳入统计分析后,各组间斑块发育的影响均不显著。重要的是,在缺乏 Cre 重组酶的小鼠中,血浆胆固醇和动脉粥样硬化的变化仍然存在,这表明它们不是由 SMC 特异性 CCL2 缺失引起的,而是由浮动等位基因或客体基因的影响引起的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Atherosclerosis plus
Atherosclerosis plus Cardiology and Cardiovascular Medicine
CiteScore
2.60
自引率
0.00%
发文量
0
审稿时长
66 days
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信