AUTHOR=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
TITLE=Pyk2/MCU Pathway as a New Target for Reversing Atherosclerosis
JOURNAL=Frontiers in Cell and Developmental Biology
VOLUME=9
YEAR=2021
URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.651579
DOI=10.3389/fcell.2021.651579
ISSN=2296-634X
ABSTRACT=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.