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

作者：Cheng Cheng, Jie Zhang, Xiaodong Li, Fei Xue, Lei Cao, Linlin Meng, Wenhai Sui, Meng Zhang, Yuxia Zhao, Bo Xi, Xiao Yu, Feng Xu, Jianmin Yang, Yun Zhang, Cheng Zhang · 发表于：Signal Transduction and Targeted Therapy · 年份：2023 · DOI：10.1038/s41392-023-01560-y · 被引用次数：65 · 研究领域：Nitric Oxide and Endothelin Effects、Atherosclerosis and Cardiovascular Diseases、Cardiovascular, Neuropeptides, and Oxidative Stress Research

Abstract 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 res...