Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension
Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium channel in hypertension
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Rbfox1 减少通过动态调节高血压中 CaV1.2 钙通道的选择性剪接来增加血管收缩
DOI：
10.1042/cs20220226
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发表时间：
2022
期刊：
影响因子：
6
通讯作者：
Juejin Wang
中科院分区：
文献类型：
--
作者：
Miaomiao Song;Wei Hou;Atta Ul Mustafa;Pengpeng Li;Jianzhen Lei;Yingying Zhou;Li Ji;Yu Sun;Hongmei Zhou;Yinyan Xu;Juejin Wang
去极化CaV1.2钙通道的钙内流触发血管平滑肌细胞（VSMC）的收缩，这对于维持血管肌源性张力和血压是重要的。CaV1.2通道的功能受选择性剪接（alternative splicing，AS）的微妙调控，其异常剪接参与多种心血管疾病的发病机制。RNA结合蛋白Rbfox 1在神经元发育过程中参与调节CaV1.2通道的AS事件，但其在血管CaV1.2通道和血管收缩中的作用尚不清楚。在此，我们检测到Rbfox 1在大鼠血管平滑肌中的表达。此外，Rbfox 1的蛋白水平显着降低，在高血压的小动脉自发性高血压大鼠相比，血压正常的Wistar-Kyoto大鼠。在VSMCs中，Rbfox 1可以动态调节CaV1.2外显子9和33的AS。通过全细胞膜片钳技术，我们证实Rbfox 1基因敲低可诱导VSMCs的CaV1.2电流-电压关系曲线超极化。此外，siRNA介导的Rbfox 1的敲低增加了K+诱导的大鼠肠系膜动脉收缩。总之，我们的研究结果表明Rbfox 1通过动态调节CaV1.2替代外显子9和33来调节血管收缩。因此，我们的工作阐明了CaV1.2通道调节的潜在机制，并为高血压提供了潜在的治疗靶点。
Calcium influx from depolarized CaV1.2 calcium channels triggers the contraction of vascular smooth muscle cells (VSMCs), which is important for maintaining vascular myogenic tone and blood pressure. The function of CaV1.2 channel can be subtly modulated by alternative splicing (AS), and its aberrant splicing involves in the pathogenesis of multiple cardiovascular diseases. The RNA binding protein Rbfox1 is reported to regulate the AS events of CaV1.2 channel in the neuronal development, but its potential roles in vascular CaV1.2 channels and vasoconstriction remain undefined. Here, we detect Rbfox1 is expressed in rat vascular smooth muscles. Moreover, the protein level of Rbfox1 is dramatically decreased in the hypertensive small arteries from spontaneously hypertensive rats in comparison to normotensive ones from Wistar-Kyoto rats. In VSMCs, Rbfox1 could dynamically regulate the AS of CaV1.2 exons 9 and 33. By whole-cell patch clamp, we identify knockdown of Rbfox1 induces the hyperpolarization of CaV1.2 current-voltage relationship curve in VSMCs. Furthermore, siRNA-mediated knockdown of Rbfox1 increases the K+-induced constriction of rat mesenteric arteries. In summary, our results indicate Rbfox1 modulates vascular constriction by dynamically regulating CaV1.2 alternative exons 9 and 33. Therefore, our work elucidates the underlying mechanisms for CaV1.2 channels regulation and provides a potential therapeutic target for hypertension.