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.
Yingzhen Zhang  1  2 ,  Xiaoli Yang  1  3 ,  Zhongzhong Li  1 ,  Kailin Bu  1 ,  Tong Li  1 ,  Zhizhao Ma  4 ,  Binbin Wang  1 ,  Lina Ma  1 ,  Honglin Lu  1 ,  Kun Zhang  1 ,  Luji Liu  1 ,  Yanying Zhao  1 ,  Yipu Zhu  1 ,  Jin Qin  1 ,  Junzhao Cui  1 ,  Lin Liu  1 ,  Shuxia Liu  2 ,  Ping Fan  2 ,  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.
PMID: 34026753 DOI: 10.3389/fcell.2021.651579
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.
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