Pyk2/MCU Pathway as a New Target for Reversing Atherosclerosis

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作者：Zhang Yingzhen, Yang Xiaoli, Li Zhongzhong, Bu Kailin, Li Tong, Ma Zhizhao, Wang Binbin, Ma Lina, Lu Honglin, Zhang Kun, Liu Luji, Zhao Yanying, Zhu Yipu, Qin Jin, Cui Junzhao, Liu Lin, Liu Shuxia, Fan Ping, Liu Xiaoyun
期刊：Frontiers in Cell and Developmental Biology
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Objective: Multiple mechanisms including vascular endothelial cell damage have a critical role in the formation and development of atherosclerosis (AS), but the specific molecular mechanisms are not exactly clarified. This study aims to determine the possible roles of proline-rich tyrosine kinase 2 (Pyk2)/mitochondrial calcium uniporter (MCU) pathway in AS mouse model and H₂O₂-induced endothelial cell damage model and explore its possible mechanisms. Approach and Results: The AS mouse model was established using apolipoprotein E-knockout (ApoE^-/-) mice that were fed with a high-fat diet. It was very interesting to find that Pyk2/MCU expression was significantly increased in the artery wall of atherosclerotic mice and human umbilical vein endothelial cells (HUVECs) attacked by hydrogen peroxide (H₂O₂). In addition, down-regulation of Pyk2 by short hairpin RNA (shRNA) protected HUVECs from H₂O₂ insult. Furthermore, treatment with rosuvastatin on AS mouse model and H₂O₂-induced HUVEC injury model showed a protective effect against AS by inhibiting the Pyk2/MCU pathway, which maintained calcium balance, prevented the mitochondrial damage and reactive oxygen species production, and eventually inhibited cell apoptosis. Conclusion: Our results provide important insight into the initiation of the Pyk2/MCU pathway involved in AS-related endothelial cell damage, which may be a new promising target for atherosclerosis intervention.