Pyk2/MCU Pathway as a New Target for Reversing Atherosclerosis

Yingzhen Zhang; Xiaoli Yang; Zhongzhong Li; Kailin Bu; Tong Li; Zhizhao Ma; Binbin Wang; Lina Ma; Honglin Lu; Kun Zhang; Luji Liu; Yanying Zhao; Yipu Zhu; Jin Qin; Junzhao Cui; Lin Liu; Shuxia Liu; Ping Fan; Xiaoyun Liu

doi:10.3389/fcell.2021.651579

Pyk2/MCU Pathway as a New Target for Reversing Atherosclerosis

Front Cell Dev Biol. 2021 May 6:9:651579. doi: 10.3389/fcell.2021.651579. eCollection 2021.

Authors

Yingzhen Zhang^{1

2}, Xiaoli Yang^{1

3}, Zhongzhong Li¹, Kailin Bu¹, Tong Li¹, Zhizhao Ma⁴, Binbin Wang¹, Lina Ma¹, Honglin Lu¹, Kun Zhang¹, Luji Liu¹, Yanying Zhao¹, Yipu Zhu¹, Jin Qin¹, Junzhao Cui¹, Lin Liu¹, Shuxia Liu², Ping Fan², Xiaoyun Liu^{1

5}

Affiliations

¹ Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
² Department of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
³ Affiliated Hospital of Hebei University of Engineering, Handan, China.
⁴ Neurosurgery Department, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
⁵ Neuroscience Research Center, Medicine and Health Institute, Hebei Medical University, Shijiazhuang, China.

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.

Keywords: ApoE–/– mice; HUVECs; Pyk2/MCU; atherosclerosis; mitochondrion.