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HSP20 phosphorylation and airway smooth muscle relaxation

机译：HSP20磷酸化和气道平滑肌松弛

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Abstract: HSP20 (HSPB6) is a small heat shock protein expressed in smooth muscles that is hypothesized to inhibit contraction when phosphorylated by cAMP-dependent protein kinase. To investigate this hypothesis in airway smooth muscle (ASM) we showed that HSP20 was constitutively expressed as well as being inducible in cultured hASM cells by treatment with 1 μM isoproterenol or 10 μM salmeterol. In contrast, a mixture of proinflammatory mediators (interleukin-1β, tumor necrosis factor α, and interferon γ) inhibited expression of HSP20 by about 50% in 48 hours. To determine whether phosphorylation of HSP20 is sufficient to induce relaxation, canine tracheal smooth muscle was treated with a cell permeant phosphopeptide that mimics the phosphorylation of HSP20. The HSP20 phosphopeptide antagonized carbacholinduced contraction by 60% with no change in myosin light chain phosphorylation. Recombinant full length HSP20 inhibited skeletal actin binding to smooth muscle myosin subfragment 1 (S1), and recombinant cell permeant TAT-HSP20 S16D mutant reduced F-actin filaments in cultured hASM cells. Carbachol stimulation of canine tracheal smooth muscle tissue caused redistribution of HSP20 from large macromolecular complexes (200–500 kDa) to smaller complexes (<60 kDa). The results are consistent with HSP20 expression and macromolecular structure being dynamically regulated in airway smooth muscle. HSP20 is upregulated by beta agonists and downregulated by proinflammatory cytokines. HSP20 is phosphorylated in vivo in a cAMP-dependent manner and the phosphorylated form promotes airway smooth muscle relaxation, possibly through depolymerization of F-actin as well as inhibition of myosin binding to actin.
机译：摘要：HSP20（HSPB6）是在平滑肌中表达的一种小热激蛋白，据推测在被cAMP依赖性蛋白激酶磷酸化时可抑制收缩。为了研究气道平滑肌（ASM）中的这一假设，我们显示了通过用1μM异丙肾上腺素或10μM沙美特罗处理，在培养的hASM细胞中HSP20组成型表达并被诱导。相反，促炎性介质（白介素-1β，肿瘤坏死因子α和干扰素γ）的混合物在48小时内抑制HSP20的表达约50％。为了确定HSP20的磷酸化是否足以诱导松弛，用模仿HSP20磷酸化的细胞渗透性磷酸肽处理犬气管平滑肌。 HSP20磷酸肽拮抗卡巴胆碱引起的收缩60％，而肌球蛋白轻链磷酸化没有变化。重组全长HSP20抑制骨骼肌肌动蛋白与平滑肌肌球蛋白亚片段1（S1）的结合，并且重组细胞渗透性TAT-HSP20 S16D突变体减少了培养的hASM细胞中的F-肌动蛋白丝。卡巴胆碱对犬气管平滑肌组织的刺激导致HSP20从大分子复合物（200–500 kDa）重新分布到较小的复合物（<60 kDa）。结果与气道平滑肌中HSP20的表达和动态调节的大分子结构一致。 HSP20被β激动剂上调，而被促炎细胞因子下调。 HSP20在体内以cAMP依赖性方式被磷酸化，磷酸化形式可能通过F-肌动蛋白解聚以及抑制肌球蛋白与肌动蛋白的结合来促进气道平滑肌松弛。

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