NPRC 缺失通过抑制 ApoE 敲除小鼠的氧化应激、炎症和细胞凋亡来减轻动脉粥样硬化,Signal Transduction and Targeted Therapy

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NPRC 缺失通过抑制 ApoE 敲除小鼠的氧化应激、炎症和细胞凋亡来减轻动脉粥样硬化
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2023-08-09 , DOI: 10.1038/s41392-023-01560-y
Cheng Cheng _{1,

2} , Jie Zhang ₁ , Xiaodong Li ₂ , Fei Xue ₁ , Lei Cao ₁ , Linlin Meng ₁ , Wenhai Sui ₁ , Meng Zhang ₁ , Yuxia Zhao _{1,

3} , Bo Xi ₄ , Xiao Yu ₅ , Feng Xu ₆ , Jianmin Yang ₁ , Yun Zhang _{1,

7} , Cheng Zhang _{1,

7}

Affiliation

National Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China.
Department of Traditional Chinese Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
Department of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.
Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Emergency Medicine, Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China.
Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.

先前的研究表明，利钠肽对心血管疾病的动物模型具有有益作用，但利钠肽受体 C (NPRC) 在动脉粥样硬化 (AS) 发病机制中的作用仍不清楚。本研究旨在检验以下假设：NPRC 可能通过蛋白激酶 A (PKA) 信号传导增强氧化应激、炎症和细胞凋亡，从而促进 AS 病变形成和不稳定。ApoE ^-/−小鼠被喂食食物或西方饮食 12 周，西方饮食喂养的小鼠主动脉组织中 NPRC 表达显着增加。^{系统性 NPRC 敲除小鼠与 ApoE −/−}小鼠杂交产生 ApoE ^−/− NPRC ^−/−小鼠，NPRC 缺失导致 ApoE ^−/− NPRC ^−/−中主动脉粥样硬化病变的大小和不稳定性显着减小。与 ApoE ^−/−小鼠相比。此外，内皮细胞特异性 NPRC 敲除可减轻小鼠的动脉粥样硬化病变。相反，内皮细胞过度表达 NPRC 会加剧小鼠动脉粥样硬化主动脉病变的大小和不稳定性。体外实验表明，人主动脉内皮细胞（HAEC）中的 NPRC 敲低可抑制 ROS 产生、促炎细胞因子表达和内皮细胞凋亡，并增加 eNOS 表达。此外，HAEC 中的 NPRC 敲低通过对内皮细胞的影响抑制了巨噬细胞迁移、细胞因子表达和吞噬作用。相反，NPRC在内皮细胞中过度表达会产生相反的效果。从机制上讲，NPRC缺失的抗炎和抗动脉粥样硬化作用涉及cAMP/PKA通路的激活，导致下游AKT1通路上调和NF-κB通路下调。总之，NPRC 缺失通过调节 cAMP/PKA-AKT1 和 NF-κB 通路减轻炎症和内皮细胞凋亡并增加 eNOS 表达，从而减少ApoE ^{−/−小鼠动脉粥样硬化病变的大小和不稳定性。}因此，靶向 NPRC 可能为预防和治疗动脉粥样硬化提供一种有前景的方法。

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NPRC deletion mitigated atherosclerosis by inhibiting oxidative stress, inflammation and apoptosis in ApoE knockout mice

Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease, but the role of natriuretic peptide receptor C (NPRC) in the pathogenesis of atherosclerosis (AS) remains unknown. This study was designed to test the hypothesis that NPRC may promote AS lesion formation and instability by enhancing oxidative stress, inflammation, and apoptosis via protein kinase A (PKA) signaling. ApoE^−/− mice were fed chow or Western diet for 12 weeks and NPRC expression was significantly increased in the aortic tissues of Western diet-fed mice. Systemic NPRC knockout mice were crossed with ApoE^−/− mice to generate ApoE^−/−NPRC^−/− mice, and NPRC deletion resulted in a significant decrease in the size and instability of aortic atherosclerotic lesions in ApoE^−/−NPRC^−/− versus ApoE^−/− mice. In addition, endothelial cell-specific NPRC knockout attenuated atherosclerotic lesions in mice. In contrast, endothelial cell overexpression of NPRC aggravated the size and instability of atherosclerotic aortic lesions in mice. Experiments in vitro showed that NPRC knockdown in human aortic endothelial cells (HAECs) inhibited ROS production, pro-inflammatory cytokine expression and endothelial cell apoptosis, and increased eNOS expression. Furthermore, NPRC knockdown in HAECs suppressed macrophage migration, cytokine expression, and phagocytosis via its effects on endothelial cells. On the contrary, NPRC overexpression in endothelial cells resulted in opposite effects. Mechanistically, the anti-inflammation and anti-atherosclerosis effects of NPRC deletion involved activation of cAMP/PKA pathway, leading to downstream upregulated AKT1 pathway and downregulated NF-κB pathway. In conclusion, NPRC deletion reduced the size and instability of atherosclerotic lesions in ApoE^−/− mice via attenuating inflammation and endothelial cell apoptosis and increasing eNOS expression by modulating cAMP/PKA-AKT1 and NF-κB pathways. Thus, targeting NPRC may provide a promising approach to the prevention and treatment of atherosclerosis.

更新日期：2023-08-09

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