c-Kit expression in smooth muscle cells reduces atherosclerosis burden in hyperlipidemic mice.
c-Kit expression in smooth muscle cells reduces atherosclerosis burden in hyperlipidemic mice.
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c-Kit在平滑肌细胞中的表达降低了高脂血症小鼠的动脉粥样硬化负担。
DOI：
10.1016/j.atherosclerosis.2021.03.004
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发表时间：
2021-05
期刊：
影响因子：
5.3
通讯作者：
Vazquez-Padron RI
中科院分区：
文献类型：
--
作者：
Zigmond ZM;Song L;Martinez L;Lassance-Soares RM;Velazquez OC;Vazquez-Padron RI
受体酪氨酸激酶（RTK）活性增加历来与动脉粥样硬化有关。巧合的是，我们最近发现c-Kit功能的整体缺陷增加了高血脂小鼠的动脉粥样硬化。本研究旨在研究这种不寻常的动脉粥样硬化保护表型是否依赖于c-Kit在平滑肌细胞（SMC）中的功能。我们研究了SMC特异性条件性基因敲除小鼠（KitSMC）和对照同窝仔的动脉粥样硬化。给三苯氧胺（TAM）和赋形剂处理的小鼠喂食高脂饮食16周，然后使用油红染色评估整个主动脉中的动脉粥样硬化。通过免疫荧光共聚焦显微镜在条件性c-Kit示踪小鼠（KitSMC eYFP）及其对照同窝小鼠（KitWT eYFP）的主动脉窦内示踪平滑肌细胞。然后，我们对c-Kit缺陷小鼠和对照小鼠的原代SMC进行RNA测序，并鉴定了SMC中c-Kit缺陷导致的显著改变的基因和途径。相对于对照组，KitSMC小鼠的动脉粥样硬化显著增加。此外，SMC中c-Kit的丢失增加了高血压小鼠主动脉窦中的斑块大小和坏死核心面积。来自KitSMC eYFP小鼠的平滑肌细胞更倾向于迁移和表达泡沫细胞标志物（例如，Mac 2和MCAM）。RNAseq分析显示与细胞增殖、迁移、脂质代谢和继发于原发性SMC中Kit功能丧失的炎症相关的基因显著上调。c-Kit的缺失增加了高脂血症小鼠动脉粥样硬化斑块中SMC的迁移、增殖和泡沫细胞标志物的表达。
Increased receptor tyrosine kinase (RTK) activity has been historically linked to atherosclerosis. Paradoxically, we recently found that global deficiency in c-Kit function increased atherosclerosis in hyperlipidemic mice. This study aimed to investigate if such unusual atheroprotective phenotype depends upon c-Kit’s function in smooth muscle cells (SMC). We studied atherosclerosis in a SMC-specific conditional knockout mice (KitSMC) and control littermate. Tamoxifen (TAM) and vehicle treated mice were fed high fat diet for 16 weeks before atherosclerosis assessment in the whole aorta using oil red staining. Smooth muscle cells were traced within the aortic sinus of conditional c-Kit tracing mice (KitSMC eYFP) and their control littermates (KitWT eYFP) by immunofluorescent confocal microscopy. We then performed RNA sequencing on primary SMC from c-Kit deficient and control mice, and identified significantly altered genes and pathways as a result of c-Kit deficiency in SMC. Atherosclerosis significantly increased in KitSMC mice with respect to control groups. In addition, the loss of c-Kit in SMC increased plaque size and necrotic core area in the aortic sinus of hyperlipidemic mice. Smooth muscle cells from KitSMC eYFP mice were more prone to migrate and express foam cell markers (e.g., Mac2 and MCAM) than those from control littermate animals. RNAseq analysis showed a significant upregulation in genes associated with cell proliferation, migration, lipid metabolism, and inflammation secondary to the loss of Kit function in primary SMCs. Loss of c-Kit increases SMC migration, proliferation, and expression of foam cell markers in atherosclerotic plaques from hyperlipidemic mice.
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DOI：
10.1161/atvbaha.110.221135
发表时间：
2011-07
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Mack CP
通讯作者：
Mack CP
DOI：
10.1073/pnas.89.2.678
发表时间：
1992-01-15
影响因子：
11.1
作者：
LEV, S;GIVOL, D;YARDEN, Y
通讯作者：
YARDEN, Y
DOI：
10.1161/01.atv.0000247243.48542.9d
发表时间：
2006-12-01
影响因子：
8.7
作者：
Bentzon, Jacob F.;Weile, Charlotte;Falk, Erling
通讯作者：
Falk, Erling
巨噬细胞 CD146 促进动脉粥样硬化期间泡沫细胞的形成和保留
影响因子：
44.1
作者：
Luo Y;Duan H;Qian Y;Feng L;Wu Z;Wang F;Feng J;Yang D;Qin Z;Yan X
通讯作者：
Yan X
影响因子：
9.2
作者：
Liang J;Wu YL;Chen BJ;Zhang W;Tanaka Y;Sugiyama H
通讯作者：
Sugiyama H