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.
Highlights
Atherosclerosis (AS) is the leading cause of cardiovascular and cerebrovascular disorders such as myocardial infarction and brain stroke (Huang et al, 2019)
Based on the abovementioned results, we considered that the proline-rich tyrosine kinase 2 (Pyk2)/mitochondrial calcium uniporter (MCU) pathway activity is upregulated during atherosclerosis and suppressed by rosuvastatin at some levels
In order to further examine whether the Pyk2/MCU pathway is a target for reversing atherosclerosis, we investigated the changes in Pyk2 and MCU at the transcript level and protein level on cell models (Figure 6)
Summary
Atherosclerosis (AS) is the leading cause of cardiovascular and cerebrovascular disorders such as myocardial infarction and brain stroke (Huang et al, 2019). Dysregulation of lipid metabolism and inflammatory processes that involve the binding of monocytes to dysfunctional endothelium, their recruitment to susceptible areas of the arterial wall, and their differentiation to macrophages and development into foam cells have been associated with atherosclerosis formation (Yu et al, 2018). Several other pathogeneses of atherosclerosis have been suggested, including lipid infiltration theory, thrombosis theory, and smooth muscle cell cloning theory. The change of intracellular Ca2+ concentration ([Ca2+]i) has an important role in ECs’ functions (Alevriadou et al, 2017). Fluctuations in Ca2+ concentration are translated into the production of cellular signals, while [Ca2+]i transients are defined and shaped by the mitochondria. Ca2+ homeostasis regulates numerous cell functions, including energy metabolism, reactive oxygen species (ROS) generation, spatiotemporal dynamics of Ca2+ signaling, cell growth, and cell death. The mitochondria are highly specialized in this context because of their sponge-like retentive capacity with calcium balance (Smith and Gallo, 2018)
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