Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis.

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.

• Authors: Lele Cheng, Liang Wang, Manyun Guo, Jinlong He, Yangyang Deng, Junhui Liu, Yuanyuan Wei, Chen Wang, Juan Zhou, Li Ma, Qing Song, Zuyi Yuan, Yue Wu
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 134 Issue 13 Pg. 1805-1819 (07 17 2020) ISSN: 1470-8736 [Electronic] England
• PMID: 32639009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• C-Reactive Protein
• Metformin
• Nitric Oxide Synthase Type III
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Animals, Genetically Modified
• Blood Pressure
• C-Reactive Protein (genetics, metabolism)
• Endothelial Cells (metabolism)
• Humans
• Hypertension (drug therapy, enzymology, genetics, metabolism)
• Male
• Metformin (administration & dosage)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Signal Transduction