RESUMO
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.
Assuntos
Movimento Celular , Kisspeptinas , Miócitos de Músculo Liso , Fator de Crescimento Derivado de Plaquetas , Receptores de Kisspeptina-1 , Transdução de Sinais , Proteína rhoA de Ligação ao GTP , Humanos , Movimento Celular/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Kisspeptinas/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Receptores de Kisspeptina-1/metabolismo , Receptores de Kisspeptina-1/genética , Proteína rhoA de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Remodelação das Vias Aéreas , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células Cultivadas , Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Proliferação de CélulasRESUMO
Asthma is a multifactorial disease of origin characterized by airway hyperresponsiveness (AHR) and airway remodeling. Several pieces of evidence from other pathologies suggest that Kisspeptins (Kp) regulate cell proliferation, migration, and invasion, mechanisms that are highly relevant to asthma. Our recent in vitro studies show Kp-10 (active peptide of Kp), via its receptor, KISS1R, inhibits human airway smooth muscle cell proliferation. Here, we hypothesize a crucial role for Kp-10 in regulating AHR and airway remodeling in vivo. Utilizing C57BL/6J mice, we assessed the effect of chronic intranasal Kp-10 exposure on mixed allergen (MA)-induced mouse model of asthma. MA-challenged mice showed significant deterioration of lung function compared to those exposed to vehicle (DPBS); Kp-10 treatment significantly improved the MA-altered lung functions. Mice treated with Kp-10 alone did not show any notable changes in lung functions. MA-exposed mice showed a significant reduction in KISS1R expression as compared to vehicle alone. MA-challenged mice showed significant alterations in immune cell infiltration in the airways and remodeling changes. Proinflammatory cytokines were significantly increased upon MA exposure, an effect abrogated by Kp-10 treatment. Furthermore, biochemical and histological studies showed Kp-10 exposure significantly reduced MA-induced smooth muscle mass and soluble collagen in the lung. Overall, our findings highlight the effect of chronic Kp-10 exposure in regulating MA-induced AHR and remodeling. © 2023 The Pathological Society of Great Britain and Ireland.
