Human urinary kininogenase reduces the endothelial injury by inhibiting Pyk2/MCU pathway

2024-10-09 46

Affiliations

• Department of Neurology, The Second Hospital of Hebei Medical University, 215 West Heping Road, Shijiazhuang, Hebei 050000, China; Department of Neurology, Affiliated Hospital of Hebei University of Engineering, 81 Congtai Road, Handan, Hebei 056002, China.
• Department of Neurology, The Second Hospital of Hebei Medical University, 215 West Heping Road, Shijiazhuang, Hebei 050000, China.
• Department of Neurology, The Second Hospital of Hebei Medical University, 215 West Heping Road, Shijiazhuang, Hebei 050000, China; Department of Neurology, Xingtai People's Hospital, 16 Hongxing Street, Xingtai, Hebei 054031, China.
• Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, Hebei 050000, China.
• Department of Neurology, The Second Hospital of Hebei Medical University, 215 West Heping Road, Shijiazhuang, Hebei 050000, China. tandyshine@163.com.
• Department of Neurology, The Second Hospital of Hebei Medical University, 215 West Heping Road, Shijiazhuang, Hebei 050000, China; Neuroscience Research Center, Medicine and Health Institute, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei 050000, China. audrey-l@163.com.

PMID:  34543986 DOI: 10.1016/j.biopha.2021.112165

Abstract

The injury of endothelial cells is one of the initiating factors in restenosis after endovascular treatment. Human urinary kallidinogenase (HUK) is a tissue kallikrein which is used for ischemia-reperfusion injury treatment. Studies have shown that HUK may be a potential therapeutic agent to prevent stenosis after vascular injury, however, the precise mechanisms have not been fully established.

This study is to investigate whether HUK can protect endothelial cells after balloon injury or H₂O₂-induced endothelial cell damage through the proline-rich tyrosine kinase 2 (Pyk2)/mitochondrial calcium uniporter (MCU) pathway. Intimal hyperplasia, a decrease of pinocytotic vesicles and cell apoptosis were found in the common carotid artery balloon injury and H₂O₂-induced endothelial cell damage, Pyk2/MCU was also up-regulated in such pathological process.

HUK could prevent these injuries partially via the bradykinin B2 receptor by inhibiting Pyk2/MCU pathway, which prevented the mitochondrial damage, maintained calcium balance, and eventually inhibited cell apoptosis. Furthermore, MCU expression was not markedly increased if Pyk2 was suppressed by shRNA technique in the H₂O₂-treatment group, and cell viability was significantly better than H₂O₂-treated only.

In short, our results indicate that the Pyk2/MCU pathway is involved in endothelial injury induced by balloon injury or H₂O₂-induced endothelial cell damage. HUK plays an protective role by inhibiting the Pyk2/MCU pathway in the endothelial injury.

Keywords: Balloon injury; Endothelial injury; Human urinary kininogenase; Hydrogen peroxide; MCU; Pyk2.