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Abstract：
Airway remodeling is a cardinal feature of asthma, associated with increased airway smooth muscle (ASM) cell mass and upregulation of extracellular matrix deposition. Exaggerated ASM cell migration contributes to excessive ASM mass. Previously, we demonstrated the alleviating role of Kp (kisspeptin) receptor (KISS1R) activation by Kp-10 in mitogen (PDGF [platelet-derived growth factor])-induced human ASM cell proliferation in vitro and airway remodeling in vivo in a mouse model of asthma. Here, we examined the mechanisms by which KISS1R activation regulates mitogen-induced ASM cell migration. KISS1R activation using Kp-10 significantly inhibited PDGF-induced ASM cell migration, further confirmed using KISS1R shRNA. Furthermore, KISS1R activation modulated F/G actin dynamics and the expression of promigration proteins like CDC42 (cell division control protein 42) and cofilin. Mechanistically, we observed reduced ASM RhoA-GTPAse with KISS1R activation. The antimigratory effect of KISS1R was abolished by PKA (protein kinase A)-inhibitory peptide. Conversely, KISS1R activation significantly increased cAMP and phosphorylation of CREB (cAMP-response element binding protein) in PDGF-exposed ASM cells. Overall, these results highlight the alleviating properties of Kp-10 in the context of airway remodeling.
摘要：
气道重塑是哮喘的主要特征，与气道平滑肌（ASM）细胞量增加和细胞外基质沉积上调有关。过度的ASM细胞迁移有助于过度的ASM质量。以前,在哮喘小鼠模型中,我们证明了Kp-10激活Kp(kisspeptin)受体(KISS1R)在促分裂原(PDGF[血小板衍生生长因子])诱导的人ASM细胞体外增殖和体内气道重塑中的缓解作用.这里,我们研究了KISS1R激活调节丝裂原诱导的ASM细胞迁移的机制。使用Kp-10激活KISS1R显着抑制PDGF诱导的ASM细胞迁移，使用KISS1RshRNA进一步证实。此外，KISS1R激活调节F/G肌动蛋白动力学和前迁移蛋白如CDC42(细胞分裂控制蛋白42)和cofilin的表达。机械上,我们观察到具有KISS1R激活的ASMRhoA-GTPose降低。PKA（蛋白激酶A）抑制肽消除了KISS1R的抗迁移作用。相反，KISS1R激活显着增加暴露于PDGF的ASM细胞中cAMP和CREB（cAMP反应元件结合蛋白）的磷酸化。总的来说,这些结果突出了Kp-10在气道重塑中的缓解特性。
