Pyk2/MCU pathway as a new target for reversing atherosclerosis

2024-10-09 39

Affiliations

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

PMID:  34026753 PMCID: PMC8134689 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.