DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells
| Autor: | Guizhu Liu, Qiangyou Wan, Fotini Gounari, Ankang Lyu, Deping Kong, Qian Liu, Sheng-Zhong Duan, Richard M. Breyer, Peiyuan Bai, Juanjuan Li, Ying Yu, Michael Lazarus, Bin Zhou, Shengkai Zuo, Chenchen Wang |
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| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
Aging medicine.medical_specialty Sp1 Transcription Factor Nedd4 Ubiquitin Protein Ligases Lymphocyte Receptors Prostaglandin 030204 cardiovascular system & hematology Article Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Superoxides Physiology (medical) Internal medicine Age related medicine Animals Humans Antihypertensive Agents Aged 030304 developmental biology NEDD4L 0303 health sciences Prostaglandin D2 business.industry Ubiquitination Th1 Cells Cyclic AMP-Dependent Protein Kinases Mice Inbred C57BL Blood pressure medicine.anatomical_structure Endocrinology Hypertension Cytokines T-Box Domain Proteins Cardiology and Cardiovascular Medicine business Signal Transduction |
| Zdroj: | Circulation |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.119.042532 |
| Popis: | Background: Blood pressure often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of proinflammatory cytokines increases in T lymphocytes. Prostaglandin D 2 , a proresolution mediator, suppresses Type 1 T helper (Th1) cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of the prostaglandin D 2 /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, prostaglandin production, and Western blot assays. Mice blood pressure was quantified by invasive telemetric monitor. Results: The prostaglandin D 2 /DP1 axis was downregulated in CD4 + T cells from older humans and aged mice. DP1 deletion in CD4 + T cells augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling, CD4 + T cells infiltration, and 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. Tumor necrosis factor α neutralization or interferon γ deletion ameliorated the age-related hypertension in DP1 deletion in CD4 + T cells mice. Mechanistically, DP1 inhibited Th1 activity via the PKA (protein kinase A)/p-Sp1 (phosphorylated specificity protein 1)/neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) pathway–mediated T-box-expressed-in-T-cells (T-bet) ubiquitination. T-bet deletion or forced NEDD4L expression in CD4 + T cells attenuated age-related hypertension in CD4 + T cell–specific DP1-deficient mice. DP1 receptor activation by BW245C prevented age-associated blood pressure elevation and reduced vascular/renal superoxide production in male mice. Conclusions: The prostaglandin D 2 /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. |
| Databáze: | OpenAIRE |
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