Cholesterol-Induced Phenotypic Modulation of Smooth Muscle Cells to Macrophage/Fibroblast-like Cells Is Driven by an Unfolded Protein Response.
Cholesterol-Induced Phenotypic Modulation of Smooth Muscle Cells to Macrophage/Fibroblast-like Cells Is Driven by an Unfolded Protein Response.
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DOI：
10.1161/atvbaha.120.315164
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Milewicz DM
中科院分区：
文献类型：
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作者：
Chattopadhyay A;Kwartler CS;Kaw K;Li Y;Kaw A;Chen J;LeMaire SA;Shen YH;Milewicz DM
补充数字内容可在正文中找到。随着胆固醇的暴露，血管平滑肌细胞(SMCs)去分化并启动巨噬细胞标志物的表达。这种表型转换依赖于转录因子Klf4(Krüppel样因子4)。我们研究了胆固醇诱导SMC表型转换的分子途径。随着游离胆固醇的暴露，SMC减少收缩标志物的表达，激活KLF4，并上调巨噬细胞和成纤维细胞标志物的子集，这些标志物是随动脉粥样硬化斑块形成而出现的调制SMC的特征。这些表型变化与内质网未折叠蛋白反应(UPR)、PERK(蛋白激酶RNA样内质网激酶)、IRE(肌醇需要酶)1α和ATF6(激活转录因子)3条通路的激活有关。阻断胆固醇从质膜到内质网的运动可以阻止游离胆固醇诱导的UPR、KLF4激活以及大多数巨噬细胞和成纤维细胞标志物的上调。胆固醇诱导的表型转换也可以通过整体抑制UPR或特异性抑制PERK信号来防止。暴露于化学UPR诱导剂衣霉素和thapsigargin，足以诱导这些相同的表型转变。最后，对高脂血症小鼠动脉粥样硬化斑块形成过程中已发表的单细胞RNA测序数据的分析提供了初步的体内证据，证明UPR激活在调节的SMC中发挥作用。我们的数据表明，UPR是推动SMC向动脉粥样硬化斑块中发现的类似调制SMC的细胞表型转换的必要条件和充分条件。在高脂血症小鼠中预防UPR可以减少动脉粥样硬化的负担，我们的数据表明，阻止SMC向表达巨噬细胞和成纤维细胞标志物的去分化细胞转变有助于减少斑块负担。
Supplemental Digital Content is available in the text. Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. With exposure to free cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents free cholesterol–induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin and thapsigargin, is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs. Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.