Deping Kong1, Qiangyou Wan2, Juanjuan Li3, Shengkai Zuo1, Guizhu Liu4, Qian Liu1, Chenchen Wang2, Peiyuan Bai5, Sheng-Zhong Duan6, Bin Zhou7, Fotini Gounari8, Ankang Lyu5, Michael Lazarus9, Richard M Breyer10, Ying Yu1,2,4. 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, China (D.K., S.Z., Q.L., Y.Y.). 2. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (Q.W., C.W., Y.Y.), University of Chinese Academy of Sciences, Chinese Academy of Sciences, China. 3. Department of Gastroenterology (J.L.), Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China. 4. National Clinical Research Center for Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, China (G.L., Y.Y.). 5. Department of Cardiology (P.B., A.L.), Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China. 6. Laboratory of Oral Microbiology, Shanghai Research Institute of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China (S.-Z.D.). 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 (B.Z.), University of Chinese Academy of Sciences, Chinese Academy of Sciences, China. 8. Division of Rheumatology and Knapp Center for Lupus and Immunology Research, University of Chicago, IL (F.G.). 9. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City, Ibaraki, Japan (M.L.). 10. Department of Veterans Affairs, Tennessee Valley Health Authority, and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (R.M.B.).
Abstract
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 D2, 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 D2/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 D2/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 D2/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.
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 D2, 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 D2/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 D2/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 D2/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.
Authors: Heddwen L Brooks; Meredith Hay; Dennis P Pollow; Jennifer Uhrlaub; Melissa Romero-Aleshire; Kathryn Sandberg; Janko Nikolich-Zugich Journal: Hypertension Date: 2014-06-02 Impact factor: 10.190