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bioRxiv · 10.1101/2023.12.06.570377

Inhibition of KLK8 promotes pulmonary endothelial repair by restoring VE-cadherin/Akt/FOXM1 pathway

Zhao, Y.·Ji, H.·Han, F.·Xu, Q.·Zhang, H.·Liu, D.·Wei, J.·Xu, D.·Jiang, L.·Du, J.·Xu, P.·Liu, Y.·Zhu, X.
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Abstract

The tissue kallikrein-related peptidases (KLKs) are secreted serine proteases deeply involved in angiogenesis. However, whether KLKs are involved in the regulation of endothelial regeneration during sepsis remains unknown. By comparing the mRNA levels of 15 KLKs, we found that KLK8 was the highest induced KLK member in lung tissues or primary isolated mouse lung vascular endothelial cells (MLVECs) exposed to lipopolysaccharide (LPS). Adenovirus-mediated overexpression of KLK8 caused endothelial hyperpermeability both in vitro and in vivo. Inhibition of KLK8, by either gene knockout or KLK8 neutralizing antibodies, alleviated sepsis-induced endothelial hyperpermeability, acute lung injury and mortality. Mechanistically, transcription profiling of KLK8-overexpressed endothelial cells revealed a central role of forkhead box M1 (FOXM1) downregulation in mediating the pro-injury and anti-proliferation effects of KLK8. KLK8 cleaved VE-cadherin and consequently suppressed FOXM1 expression by inactivation of the VE-cadherin/Akt pathway. KLK8 deficiency or blockade rescued VE-cadherin/Akt/FOXM1 pathway, thus promoting endothelium regeneration. This study reveals a critical role for KLK8-induced inactivation of VE-cadherin/Akt/FOXM1 pathway in mediating the impairment of endothelial regeneration and the consequent lung vascular leakiness in response to sepsis. HighlightsO_LIUpregulated KLK8 mediates lung endothelial barrier dysfunction during sepsis C_LIO_LIKLK8 inactivates VE-cadherin/Akt/FOXM1, thus impairing endothelium regeneration C_LIO_LIKLK8 deficiency or blockade rescues VE-cadherin/Akt/FOXM1 signaling pathway C_LIO_LIKLK8 deficiency or blockade promotes endothelium regeneration during sepsis C_LIO_LIKLK8 deficiency or blockade attenuates sepsis-induced acute lung injury and mortality C_LI

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Zhao, Y., Ji, H., Han, F., Xu, Q., Zhang, H., Liu, D., Wei, J., Xu, D., Jiang, L., Du, J., Xu, P., Liu, Y., Zhu, X.. 2023-12-12. Inhibition of KLK8 promotes pulmonary endothelial repair by restoring VE-cadherin/Akt/FOXM1 pathway. https://doi.org/10.1101/2023.12.06.570377

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