LRP1 regulates asthmatic airway smooth muscle proliferation through FGF2/ERK signaling.

Abstract

Airway smooth muscle (ASM) hyperplasia is a hallmark of airway remodeling in asthma, which still lacks an effective treatment. Low-density lipoprotein receptor-related protein 1 (LRP1) is involved in regulating the proliferation of various cell types, and the intracellular domain of LRP1 (LRP1-ICD) also exhibits unique biological functions. However, the role of LRP1 in asthma airway remodeling remains unclear. In the present study, LRP1 was increased in ASM cells of mice with OVA-induced chronic asthma, with the elevation in LRP1-ICD protein levels being significantly greater than that of the LRP1 β chain. In vivo experiments demonstrated that inhibiting LRP1 reduced ASM proliferation in these mice. Mechanistically, LRP1 knockdown inhibited the FGF2/ERK signaling pathway, thereby arresting cell cycle progression and suppressing ASM cell proliferation. Additionally, in vitro experiments revealed that the inhibitory effect of LRP1-ICD overexpression on ASM cell proliferation was lost after adjusting the levels of LRP1. LRP1-ICD overexpression inhibited full-length LRP1 protein levels by promoting its protein degradation rather than by suppressing its transcription, thus preventing further exacerbation of asthma. In conclusion, this study clarifies the molecular biological mechanism by which LRP1 regulates ASM proliferation, suggesting targeting full-length LRP1 as a strategy for therapeutic intervention in asthma airway remodeling.