BACKGROUND:CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms.METHODS:Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE^−/−) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism.RESULTS:We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE^−/− mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain–containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation.CONCLUSIONS:Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

中文翻译：

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CNP 改善巨噬细胞炎症反应和动脉粥样硬化

背景：CNP（C型利钠肽）是利钠肽家族中的一种内源性短肽，已成为控制血管稳态的重要调节因子。然而，其在动脉粥样硬化发展中的作用仍不清楚。本研究旨在探讨CNP对动脉粥样硬化斑块进展的影响并阐明其潜在机制。方法：测定急性冠脉综合征患者血浆CNP水平。通过渗透泵补充 CNP、基因过表达或 LCZ696 给药，在载脂蛋白 E 缺陷 (ApoE ^−/− ) 小鼠中评估了 CNP 的潜在动脉粥样硬化作用。对野生型和 CD36（分化簇 36）敲除小鼠的原代巨噬细胞进行了涉及 CNP 处理的各种功能实验。通过蛋白质组学和多种生化分析来揭示其潜在机制。结果：我们观察到患者血浆CNP浓度与冠状动脉粥样硬化负担之间呈负相关。在早期动脉粥样硬化斑块中，CNP 主要积聚在巨噬细胞中，但在晚期斑块中显着减少。通过渗透泵或基因过度表达补充 CNP 可改善 ApoE ^−/−小鼠的动脉粥样硬化斑块形成并增强斑块稳定性。 CNP 促进抗炎巨噬细胞表型和胞吞作用，并减少泡沫细胞形成和坏死性凋亡。从机制上讲，我们发现CNP可以通过增强PHD（含脯氨酰羟化酶结构域的蛋白）2和HIF-1α之间的相互作用来加速巨噬细胞中HIF-1α（缺氧诱导因子1-α）的降解。此外，我们观察到 CD36 与 CNP 结合并介导其在巨噬细胞中的内吞作用。此外，我们证明，给予 LCZ696（一种最近批准用于治疗射血分数降低的慢性心力衰竭的口服生物可利用药物）可以增强 CNP 的生物活性并改善动脉粥样硬化斑块的形成。结论：我们的研究表明，CNP 增强斑块稳定性并减轻动脉粥样硬化斑块的形成。通过促进 HIF-1α 降解来抑制巨噬细胞炎症反应，表明 CNP 具有新的动脉粥样硬化保护作用。增强CNP生物活性可能为治疗相关疾病提供新的药理学策略。