Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis
Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis
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DOI：
10.1042/cs20200137
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发表时间：
2020-07-01
期刊：
影响因子：
6
通讯作者：
Wu, Yue
中科院分区：
文献类型：
--
作者：
Cheng, Lele;Wang, Liang;Wu, Yue
成功治疗伴有人类C反应蛋白（hCRP）升高的顽固性高血压仍然是降低心血管疾病负担的关键挑战。目前尚不清楚临床相关的高水平hCRP是否仅仅是高血压的标志物或关键驱动因素。本研究旨在探讨hCRP在高血压中的作用及其机制。在所有三种hCRP过表达模型中均观察到血压升高，包括腺相关病毒9（AAV 9）转染小鼠、AAV 9转染大鼠和hCRP转基因（hCRPtg）大鼠。表达临床相关高水平hCRP的hCRPtg大鼠发生自发性高血压、心脏肥大、心肌纤维化和内皮依赖性舒张功能受损。在机制上，在用AAV 9-hCRP转染的内皮一氧化氮（NO）合酶（eNOS）敲除小鼠中的研究和hCRP处理的内皮细胞的磷酸化蛋白质组学分析显示，hCRP抑制AMP活化蛋白激酶（AMPK）-eNOS磷酸化途径。此外，二甲双胍激活AMPK使hCRPtg大鼠的内皮依赖性血管舒张正常化并降低血压。我们的研究结果表明，临床相关的高水平hCRP通过抑制AMPK-eNOS信号转导诱导高血压和内皮功能障碍，并强调hCRP不仅是一种炎症生物标志物，也是高血压的驱动因素。二甲双胍或合成AMPK激活剂治疗可能是hCRP水平高的患者血管功能障碍和高血压的潜在策略。
Successful treatment of resistant hypertension accompanied by elevated human C-reactive protein (hCRP) remains a key challenge in reducing the burden of cardiovascular diseases. It is still unclear whether clinically relevant high-level hCRP is merely a marker or a key driver of hypertension. Here, we investigated the role and mechanism of clinically relevant high level of hCRP in hypertension. Elevated blood pressure was observed in all three hCRP overexpression models, including adeno-associated virus 9 (AAV9)-transfected mice, AAV9-transfected rats and hCRP transgenic (hCRPtg) rats. hCRPtg rats expressing clinically relevant high-level hCRP developed spontaneous hypertension, cardiac hypertrophy, myocardial fibrosis and impaired endothelium-dependent relaxation. Mechanistically, studies in endothelial nitric oxide (NO) synthase (eNOS) knockout mice transfected with AAV9-hCRP and phosphoproteomics analysis of hCRP-treated endothelial cells revealed that hCRP inhibited AMP-activated protein kinase (AMPK)-eNOS phosphorylation pathway. Further, activation of AMPK by metformin normalized endothelial-dependent vasodilation and decreased the blood pressure of hCRPtg rats. Our results show that clinically relevant high-level hCRP induces hypertension and endothelial dysfunction by inhibiting AMPK-eNOS signaling, and highlight hCRP is not only an inflammatory biomarker but also a driver of hypertension. Treatment with metformin or a synthetic AMPK activator may be a potential strategy for vaso-dysfunction and hypertension in patients with high hCRP levels.