PMID- 32639009 OWN - NLM STAT- MEDLINE DCOM- 20210201 LR - 20210201 IS - 1470-8736 (Electronic) IS - 0143-5221 (Linking) VI - 134 IP - 13 DP - 2020 Jul 17 TI - Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis. PG - 1805-1819 LID - 10.1042/CS20200137 [doi] AB - 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. CI - (c) 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. FAU - Cheng, Lele AU - Cheng L AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. AD - Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA, U.S.A. FAU - Wang, Liang AU - Wang L AD - Department of Vascular Surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China. FAU - Guo, Manyun AU - Guo M AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. FAU - He, Jinlong AU - He J AD - Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China. FAU - Deng, Yangyang AU - Deng Y AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. FAU - Liu, Junhui AU - Liu J AD - Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. FAU - Wei, Yuanyuan AU - Wei Y AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. FAU - Wang, Chen AU - Wang C AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. FAU - Zhou, Juan AU - Zhou J AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. FAU - Ma, Li AU - Ma L AD - Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA, U.S.A. FAU - Song, Qing AU - Song Q AD - Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA, U.S.A. FAU - Yuan, Zuyi AU - Yuan Z AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. FAU - Wu, Yue AU - Wu Y AD - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. AD - Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. LA - eng GR - SC2 HL095098/HL/NHLBI NIH HHS/United States GR - P50 HL117929/HL/NHLBI NIH HHS/United States GR - RC4 MD005964/MD/NIMHD NIH HHS/United States GR - U54 MD007588/MD/NIMHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - 9007-41-4 (C-Reactive Protein) RN - 9100L32L2N (Metformin) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/genetics/*metabolism MH - Animals MH - Animals, Genetically Modified MH - Blood Pressure MH - C-Reactive Protein/genetics/*metabolism MH - Endothelial Cells/*metabolism MH - Humans MH - Hypertension/drug therapy/enzymology/genetics/*metabolism MH - Male MH - Metformin/administration & dosage MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nitric Oxide Synthase Type III/genetics/*metabolism MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction OTO - NOTNLM OT - endothelial dysfunction OT - human C-reactive protein OT - hypertension EDAT- 2020/07/09 06:00 MHDA- 2021/02/02 06:00 CRDT- 2020/07/09 06:00 PHST- 2020/02/05 00:00 [received] PHST- 2020/07/05 00:00 [revised] PHST- 2020/07/08 00:00 [accepted] PHST- 2020/07/09 06:00 [pubmed] PHST- 2021/02/02 06:00 [medline] PHST- 2020/07/09 06:00 [entrez] AID - 225722 [pii] AID - 10.1042/CS20200137 [doi] PST - ppublish SO - Clin Sci (Lond). 2020 Jul 17;134(13):1805-1819. doi: 10.1042/CS20200137.