LRP1 regulates asthmatic airway smooth muscle proliferation through FGF2/ERK signaling
Ya Deng, Jiaying Zhao, Chen Gong, Wenqian Ding, Lulu Fang, Huaqing Liu, Ming Li, Bing Shen, Shenggang Ding
Ya Deng, Jiaying Zhao, Chen Gong, Wenqian Ding, Lulu Fang, Huaqing Liu, Ming Li, Bing Shen, Shenggang Ding
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Research Article Cell biology Pulmonology

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.

Authors

Ya Deng, Jiaying Zhao, Chen Gong, Wenqian Ding, Lulu Fang, Huaqing Liu, Ming Li, Bing Shen, Shenggang Ding

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Figure 8

LRP1-ICD overexpression promotes protein degradation of the LRP1 via the lysosomal pathway.

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LRP1-ICD overexpression promotes protein degradation of the LRP1 via the...
(A) HBSMCs were transfected with recombinant plasmids overexpressing LRP1-ICD (LRP1-ICD) or empty vector (Vector). Summary data showing the relative expression levels of LRP1 mRNA in indicated cells. GAPDH was used as an internal reference (n = 9). (B and C) After HBSMCs were transfected with the target plasmid (LRP1-ICD) or empty vector (Vector) for 48 hours, the cells were treated with cycloheximide (CHX) (100 μg/mL) and harvested at different time points after treatment (0, 3, 6, 9, and 12 hours). Representative immunoblot images (B) and summary data (C) showing LRP1 protein levels (n = 6). (D and E) After HBSMCs were transfected with the target plasmid (LRP1-ICD) or empty vector (Vector) for 48 hours, the cells were treated with DMSO or MG-132 (10 μM) for 12 hours. Representative immunoblot images (D) and summary data (E) showing LRP1 protein levels (n = 5). (F and G) After HBSMCs were transfected with the target plasmid (LRP1-ICD) or empty vector (Vector) for 48 hours, the cells were treated with DMSO or bafilomycin A1 (BafA1, 200 nM) for 12 hours. Representative immunoblot images (F) and summary data (G) showing LRP1 protein levels (n = 5). All data were analyzed using independent-sample t tests or 2-way ANOVA and are presented as means ± SEMs. **P < 0.01, ***P < 0.001.