Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis. Issue 13 (17th July 2020)

• Record Type: Journal Article
• Authors: Cheng, Lele; Wang, Liang; Guo, Manyun; He, Jinlong; Deng, Yangyang; Liu, Junhui; Wei, Yuanyuan; Wang, Chen; Zhou, Juan; Ma, Li; Song, Qing; Yuan, Zuyi; Wu, Yue
• Is Part Of: Clinical science. Volume 134:Issue 13(2020)
• Page Start: 1805
• Page End: 1819
• Publication Date: 2020-07-17
• Subjects: endothelial dysfunction -- human C-reactive protein -- hypertension; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20200137
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: 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.