Activation of PBK by Gal-3 contributes to pulmonary artery hypertension by promoting PRC1 activation

Galactose lectin-3 (Gal-3) has been shown to promote the progression of pulmonary arterial hypertension (PAH), yet the intricate molecular mechanisms are still unclear. Primary cultured rat pulmonary arterial smooth muscle cells (PASMCs) and PAH rats were used in this study. Protein phosphorylation and expression levels were identified using Western blotting, while mRNA level was quantified through qRT-PCR. Hemodynamic measurements, hematoxylin-eosin and immunohistochemistry staining were employed to assess the PAH progression. Yes-associated protein 1 (YAP1) mediated Gal-3/toll-like receptor 4 (TLR4)-induced PDZ-binding kinase (PBK) upregulation. Furthermore, polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) mediated Gal-3/TLR4-induced PBK phosphorylation. Activated PBK further phosphorylated protein regulator of cytokinesis 1 (PRC1), which ultimately led to PASMC proliferation. In monocrotaline-induced PAH rat models, inhibition of Gal-3, TLR4, YAP1, CDK1 or silencing of PLK1, PBK, PRC1 attenuated PAH progression. Our study presents novel evidence that Gal-3 promotes PASMC proliferation and pulmonary vascular remodeling by activating PBK/PRC1 through the TLR4/YAP1 and TLR4/PLK1/CDK1 signaling pathways, suggesting that this signaling pathway might be a promising target for the treatment of PAH.