Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.
Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.
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DOI：
10.1093/cvr/cvab156
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发表时间：
2021-04
影响因子：
10.8
通讯作者：
Jiao‐Hui Wu;Lisheng Zhang;Igor Nepliouev;L. Brian;Taiqin Huang;Kamie P Snow;B. Schickling;E. Hauser;F. Miller;N. Freedman;Jonathan A Stiber
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文献类型：
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作者：
Jiao‐Hui Wu;Lisheng Zhang;Igor Nepliouev;L. Brian;Taiqin Huang;Kamie P Snow;B. Schickling;E. Hauser;F. Miller;N. Freedman;Jonathan A Stiber
目的F-肌动蛋白结合蛋白Dreplastin抑制平滑肌细胞（SMC）迁移、增殖和促炎信号传导。因此，我们测试了Dredrone抑制动脉粥样硬化的假设。方法和结果：将SM 22-Cre+/Dbnflox/flox/Ldlr-/-（SMC-Dbn-/-/Ldlr-/-）和对照小鼠（SM 22-Cre+/Ldlr-/-、Dbnflox/flox/Ldlr-/-和Ldlr-/-）饲喂西方饮食14-20周。SMC-Dbn-/-/Ldlr-/-小鼠的头臂动脉在第14周或第20周分别表现出比对照小鼠大1.5倍或1.8倍的横截面病变面积。SMC-Dbn-/-/Ldlr-/-小鼠的主动脉粥样硬化病变表面积大1.2倍。SMC-Dbn-/-/Ldlr-/-病变包括尺寸比对照小鼠大两倍的坏死核心。与其较大的坏死核心尺寸一致，SMC-Dbn-/-动脉中的病变也显示出SMC向巨噬细胞样细胞的更多转分化：分别用BODIPY或CD 68评估的1.5至2.5倍。体外数据一致：Dbn-/-SMC具有1.7倍更高水平的KLF 4，并且在胆固醇负荷时比Dbnflox/flox SMC更容易转分化为巨噬细胞样细胞，如通过CD 68和半乳糖凝集素-3的更大上调所证明的。腺病毒介导的Dreplasty拯救在Dbn-/-和Dbnflox/flox SMC中产生等同水平的巨噬细胞样转分化。在早期动脉粥样硬化形成过程中，SMC-Dbn-/-/Ldlr-/-动脉粥样硬化显示活性氧水平比对照小鼠动脉粥样硬化高1.6倍。Dbn-/-SMC中Nox 1水平高1.8倍，但KLF 4沉默后降至WT水平。化学或siRNA抑制Nox 1在Dbn-/-和Dbnflox/flox SMC中产生等同水平的巨噬细胞样转分化。结论：我们的结论是，SMC dreaming限制动脉粥样硬化通过抑制SMC Nox 1活性和SMC转分化为巨噬细胞样细胞。翻译视角Dreplasmid在血管平滑肌细胞（SMC）中大量表达，并在人类动脉粥样硬化中上调。动脉粥样硬化的一个标志是泡沫细胞的积累，泡沫细胞分泌促炎细胞因子并导致斑块不稳定。人体内的这些泡沫细胞中有很大一部分来自SMC。我们发现，平滑肌细胞脱髓鞘限制动脉粥样硬化的方式依赖于Nox 1和KLF 4减少SMC转分化为巨噬细胞样泡沫细胞。因此，旨在增加动脉粥样硬化斑块中SMC dreplastin表达的策略可能通过抑制SMC向泡沫细胞的转分化来限制动脉粥样硬化的进展并增强斑块的稳定性。
AIMS The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation and pro-inflammatory signaling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis. METHODS AND RESULTS SM22-Cre+/Dbnflox/flox/Ldlr-/- (SMC-Dbn-/-/Ldlr-/-) and control mice (SM22-Cre+/Ldlr-/-, Dbnflox/flox/Ldlr-/-, and Ldlr-/-) were fed a Western diet for 14-20 weeks. Brachiocephalic arteries of SMC-Dbn-/-/Ldlr-/- mice exhibited 1.5- or 1.8-fold greater cross-sectional lesion area than control mice at 14 or 20 wk, respectively. Aortic atherosclerotic lesion surface area was 1.2-fold greater in SMC-Dbn-/-/Ldlr-/- mice. SMC-Dbn-/-/Ldlr-/- lesions comprised necrotic cores that were two-fold greater in size than those of control mice. Consistent with their bigger necrotic core size, lesions in SMC-Dbn-/- arteries also showed more transdifferentiation of SMCs to macrophage-like cells: 1.5- to 2.5-fold greater, assessed with BODIPY or with CD68, respectively. In vitro data were concordant: Dbn-/- SMCs had 1.7-fold higher levels of KLF4 and transdifferentiated to macrophage-like cells more readily than Dbnflox/flox SMCs upon cholesterol loading, as evidenced by greater up-regulation of CD68 and galectin-3. Adenovirally mediated Drebrin rescue produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. During early atherogenesis, SMC-Dbn-/-/Ldlr-/- aortas demonstrated 1.6-fold higher levels of reactive oxygen species than control mouse aortas. The 1.8-fold higher levels of Nox1 in Dbn-/- SMCs was reduced to WT levels with KLF4 silencing. Inhibition of Nox1 chemically or with siRNA produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. CONCLUSIONS We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells. TRANSLATIONAL PERSPECTIVE Drebrin is abundantly expressed in vascular smooth muscle cells (SMCs) and is up-regulated in human atherosclerosis. A hallmark of atherosclerosis is the accumulation of foam cells that secrete pro-inflammatory cytokines and contribute to plaque instability. A large proportion of these foam cells in humans derive from SMCs. We found that SMC Drebrin limits atherosclerosis by reducing SMC transdifferentiation to macrophage-like foam cells in a manner dependent on Nox1 and KLF4. For this reason, strategies aimed at augmenting SMC Drebrin expression in atherosclerotic plaques may limit atherosclerosis progression and enhance plaque stability by bridling SMC-to-foam-cell transdifferentiation.