Involvement of BK channel in differentiation of vascular smooth muscle cells induced by mechanical stretch.
Involvement of BK channel in differentiation of vascular smooth muscle cells induced by mechanical stretch.
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DOI：
10.1016/j.biocel.2014.11.011
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Xue-Jiao Wan;Hucheng Zhao;Ping Zhang;B. Huo;Bao-rong Shen;Zhi-qiang Yan;Ying‐Xin Qi;Zong-Lai Jiang-Zong-La
中科院分区：
文献类型：
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作者：
Xue-Jiao Wan;Hucheng Zhao;Ping Zhang;B. Huo;Bao-rong Shen;Zhi-qiang Yan;Ying‐Xin Qi;Zong-Lai Jiang-Zong-La
血管平滑肌细胞（vascular smooth muscle cells, VSMCs）的分化在高血压期血管重构中起着重要的作用。在这里，我们证明了大电导钙和电压活化钾（BK）通道在这一过程中的机械生物学作用。与5%拉伸（生理性）相比，15%拉伸（病理性）诱导VSMC去分化，导致VSMC标志物表达显著降低。α-肌动蛋白、钙钙蛋白和SM22。通过膜片钳记录评估，BK通道的活性显著增加了15%的拉伸，并伴随着BK通道α-亚基在应力轴调节外显子（STREX）上的选择性剪接增加。此外，转染整个BK或STREX缺失的BK质粒表明，STREX对BK通道感知机械拉伸很重要。利用诱导内质网（ER）应激的信号素（TG）和阻断内质网应激的xbp1靶向siRNA转染，结果表明内质网应激有助于STREX拉伸诱导的选择性剪接。我们的研究结果表明，在高血压期间，病理性拉伸可能引起VSMC内质网应激，从而影响BK通道的选择性剪接和活性，从而调节VSMC的分化。
The differentiation of vascular smooth muscle cells (VSMCs), which are exposed to mechanical stretchin vivo, plays an important role in vascular remodeling during hypertension. Here, we demonstrated the mechanobiological roles of large conductance calcium and voltage-activated potassium (BK) channels in this process. In comparison with 5% stretch (physiological), 15% stretch (pathological) induced the de-differentiation of VSMCs, resulting in significantly decreased expressions of VSMC markers,i.e., α-actin, calponin and SM22. The activity of BK channels, assessed by patch clamp recording, was significantly increased by 15% stretch and was accompanied by an increased alternative splicing of BK channel α-subunit at the stress axis-regulated exons (STREX). Furthermore, transfection of whole BK or STREX-deleted BK plasmids revealed that STREX was important for BK channels to sense mechanical stretch. Using thapsigargin (TG) which induces endoplasmic reticulum (ER) stress, and xbp1-targeted siRNA transfection which blocks ER stress, the results revealed that ER stress was contribute to stretch-induced alternative splicing of STREX. Our results suggested that during hypertension, pathological stretch may induce the ER stress in VSMCs, which affects the alternative splicing and activity of BK channels, and subsequently modulates VSMC differentiation.