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Circulation. 2020 Jan 2. doi: 10.1161/CIRCULATIONAHA.119.042532. [Epub ahead of print]

DP1 Activation Reverses Age-Related Hypertension via NEDD4L-Mediated T-bet Degradation in T Cells.

Author information

1
Department of Pharmacology and Tianjin Key laboratory of inflammatory biology; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
2
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
3
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200031, China.
4
National Clinical Research Center for Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China.
5
Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200031, China.
6
Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
7
State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence on Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200011, China.
8
Division of Rheumatology and Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL.
9
International Institute for Integrative, Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City, Ibaraki 305-8575, Japan.
10
Department of Veterans Affairs, Tennessee Valley Health Authority, and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
11
Department of Pharmacology and Tianjin Key laboratory of inflammatory biology; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; National Clinical Research Center for Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China.

Abstract

Background: Blood pressure (BP) often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of pro-inflammatory cytokines increases in T lymphocyte. Prostaglandin (PG) D2, a pro-resolution mediator, suppresses Th1 cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of PGD2/DP1 axis in T cells on age-related hypertension. Methods: To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants and CD4+ T cells were sorted for gene expression, PG production and western bot assays. Mice BP was quantified by invasive telemetric monitor. Results: PGD2/DP1 axis was down-regulated in CD4+ T cells from older humans and aged mice, DP1 deletion in CD4+ T cells (TDP1KO) augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling and CD4+ T cells infiltration, superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. TNFα neutralization or IFNγ deletion ameliorated the age-related hypertension in TDP1KO mice. Mechanistically, DP1 inhibited Th1 activity via the Gαs/PKA/p-Sp1/NEDD4L pathway-mediated T-bet ubiquitination. T-bet deletion or forced NEDD4L expression in CD4+ T cell attenuated age-related hypertension in TDP1KO mice. DP1 receptor activation by BW245C prevented age-associated BP elevation and reduced vascular/renal superoxide production in male mice. Conclusions: PGD2/DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension in males.

KEYWORDS:

D-prostanoid receptor 1

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