Yuwei Zhou
Pei Wang
Tao Tao
Lisha Wei
Ye Wang
Wei Wang
Yanyan Zheng
Zhihui Jiang
Tiantian Qiu
Wei Zhao
Jie Sun
Xin Chen
Xue-Na Zhang
Min-Sheng Zhu
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School and Gulou Hospital affiliated Medical School, Nanjing University, Nanjing 210061, China
Funds: This work was supported by the National Natural Science Funding of China (31272711, 31330034, 9184910039and 3207090129 to M.S.Z). We would like to thank Wolwo Bio-Pharmaceutical. Co., Ltd. for providing biopsies from COPD rats.
Received Date: 2020-12-14
Accepted Date:2021-04-26
Rev Recd Date:2021-04-14
Publish Date:2021-06-20
Abstract
Abstract
Airway smooth muscle (ASM) has developed a mechanical adaption mechanism by which it transduces force and responds to environmental forces, which is essential for periodic breathing. Cytoskeletal reorganization has been implicated in this process, but the regulatory mechanism remains to be determined. We here observe that ASM abundantly expresses cytoskeleton regulators Limk1 and Limk2, and their expression levels are further upregulated in chronic obstructive pulmonary disease (COPD) animals. By establishing mouse lines with deletions of Limk1 or Limk2, we analyse the length-sensitive contraction, F/G-actin dynamics, and F-actin pool of mutant ASM cells. As LIMK1 phosphorylation does not respond to the contractile stimulation, LIMK1-deficient ASM develops normal maximal force, while LIMK2 or LIMK1/LIMK2 deficient ASMs show approximately 30% inhibition. LIMK2 deletion causes a significant decrease in cofilin phosphorylation along with a reduced F/G-actin ratio. As LIMK2 functions independently of cross-bridge movement, this observation indicates that LIMK2 is necessary for F-actin dynamics and hence force transduction. Moreover, LIMK2-deficient ASMs display abolishes stretching-induced suppression of 5-hydroxytryptamine (5-HT) but not acetylcholine-evoks force, which is due to the differential contraction mechanisms adopted by the agonists. We propose that LIMK2-mediated cofilin phosphorylation is required for membrane cytoskeleton reorganization that is necessary for ASM mechanical adaption including the 5-HT-evoked length-sensitive effect.Keywords: Smooth muscle,
LIM kinases,
Cofilin,
Cytoskeleton,
Length sensitive effect
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