DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells.
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.
['Kong|Deping|D|', 'Wan|Qiangyou|Q|', 'Li|Juanjuan|J|', 'Zuo|Shengkai|S|', 'Liu|Guizhu|G|', 'Liu|Qian|Q|', 'Wang|Chenchen|C|', 'Bai|Peiyuan|P|', 'Duan|Sheng-Zhong|SZ|', 'Zhou|Bin|B|', 'Gounari|Fotini|F|', 'Lyu|Ankang|A|', 'Lazarus|Michael|M|', 'Breyer|Richard M|RM|', 'Yu|Ying|Y|']
D000368:Aged D000375:Aging D000818:Animals D000959:Antihypertensive Agents D015496:CD4-Positive T-Lymphocytes D017868:Cyclic AMP-Dependent Protein Kinases D016207:Cytokines D006801:Humans D006973:Hypertension D051379:Mice D008810:Mice, Inbred C57BL D000075702:Nedd4 Ubiquitin Protein Ligases D015230:Prostaglandin D2 D011982:Receptors, Prostaglandin D015398:Signal Transduction D016329:Sp1 Transcription Factor D013481:Superoxides D020825:T-Box Domain Proteins D018417:Th1 Cells D054875:Ubiquitination
hypertension aging lymphocyte D-prostanoid receptor 1 prostaglandin (PG) D2