Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells
Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells
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内质网应激促进钙调蛋白核转位，从而激活血管平滑肌细胞的表型转换
DOI：
10.1016/j.bbrc.2022.08.069
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发表时间：
2022
影响因子：
3.1
通讯作者：
Yano Masafumi
中科院分区：
文献类型：
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作者：
Uchida Tomoyuki;Oda Tetsuro;Yamamoto Takeshi;Inamitsu Masako;Sakai Chihiro;Uchinoumi Hitoshi;Suetomi Takeshi;Nakamura Yoshihide;Okamoto Yoko;Tateda Satomi;Fujii Shohei;Tanaka Shinji;Nawata Junya;Okamura Takayuki;Kobayashi Shigeki;Yano Masafumi
背景和目的：在动脉粥样硬化中，内质网（ER）应激增加与血管平滑肌细胞（VSMCs）的表型转换密切相关。ER Ca 2+含量的耗尽是VSMC中ER应激增加的主要原因之一。Ryanodine受体（RyR）是肌浆网膜上的一个主要钙释放通道。钙调素（CaM）与RyR（CaM-RyR）结合，在正常细胞中稳定静息状态下RyR的闭合状态。CaM-RyR相互作用的缺陷可导致Ca 2+通过RyR的异常渗漏，导致Ca 2+含量降低，表明CaM-RyR相互作用的缺陷可能是ER应激增加的原因。在此，我们使用小鼠VSMCs来评估CaM-RyR是否在由ER应激引起的VSMCs表型转换中起关键作用，以及丹曲林是否增强CaM与RyR的结合亲和力，影响VSMCs表型转换。衣霉素诱导的内质网应激导致CaM从RyR中解离并易位到细胞核，从而通过激活MEF 2和KLF 5刺激表型转换。丹曲林抑制衣霉素诱导的细胞凋亡，ER应激（恢复ER Ca 2+含量），和VSMC的表型转换。苏拉明，直接解除钙调素从RyR，促进细胞核钙调素积累与平行的VSMCs表型开关，和dantrolene防止这些effects.ConclusionsWe观察到，ER应力导致钙调素易位到细胞核和驱动器的VSMCs的表型开关。因此，恢复钙调素与RyR的结合亲和力可能是动脉粥样硬化的治疗靶点。
Background and aimsIncreased endoplasmic reticulum (ER) stress is strongly associated with the phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerosis. Depletion of the ER Ca2+content is one of the leading causes of increased ER stress in VSMCs. The ryanodine receptor (RyR) is a major Ca2+release channel in the sarcoplasmic reticulum membrane. Calmodulin (CaM), which binds to RyR (CaM-RyR), stabilizes the closed state of RyR in the resting state in normal cells. Defective CaM-RyR interactions can cause abnormal Ca2+leakage through RyR, resulting in decreased Ca2+content, indicating that defective CaM-RyR interactions may be a cause of increased ER stress. Herein, we used a mouse VSMCs to assess whether CaM-RyR plays a pivotal role in VSMCs phenotypic switching, which is caused by ER stress, and whether dantrolene, which enhances the binding affinity of CaM to RyR, affects VSMCs phenotypic switching.Methods and resultsTunicamycin was used to mimic ER stressin vitro. Tunicamycin-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulated phenotypic switching through the activation of MEF2 and KLF5. Dantrolene suppressed tunicamycin-induced apoptosis, ER stress (restoring ER Ca2+content), and phenotypic switching of VSMCs. Suramin, which directly unbinds CaM from RyR, promoted nuclear CaM accumulation with parallel VSMCs phenotypic switching, and dantrolene prevented these effects.ConclusionsWe observed that ER stress causes CaM translocation to the nucleus and drives the phenotypic switching of VSMCs. Thus, restoration of the binding affinity of CaM to RyR may be a therapeutic target for atherosclerosis.