title: Involvement of BK channel in differentiation of vascular smooth muscle cells induced by mechanical stretch.
abstract: The differentiation of vascular smooth muscle cells (VSMCs), which are exposed to mechanical stretch in 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.
authors.affiliation: Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Wan
authors.affiliation: Lab of Biomechanics, Department of Engineering Mechanics, Tsinghua University, Beijing, China.
authors.forename: Hu-Cheng
authors.initials: HC
authors.lastname: Zhao
authors.affiliation: Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: School of Aerospace Engineering, Beijing Institute of Technology, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Huo
authors.affiliation: Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Bao-Rong
authors.initials: BR
authors.lastname: Shen
authors.affiliation: Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yan
authors.affiliation: Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China. Electronic address: qiyx@sjtu.edu.cn.
authors.forename: Ying-Xin
authors.initials: YX
authors.lastname: Qi
authors.affiliation: Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zong-Lai
authors.initials: ZL
authors.lastname: Jiang
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005091:Exons / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D051036:Large-Conductance Calcium-Activated Potassium Channels; D021122:Protein Subunits; D019284:Thapsigargin; D002118:Calcium
keywords: BK channel; Differentiation; Endoplasmic reticulum stress; Mechanical stretch; Vascular smooth muscle cells