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.

中文翻译：

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DP1激活通过NEDD4L介导的T细胞在T细胞中的降解而逆转与年龄有关的高血压

背景：血压通常会随着年龄的增长而上升，但确切的机制仍不完全清楚。随着年龄的增长，T淋巴细胞中促炎细胞因子的水平增加。前列腺素D ₂是一种高分辨率的介体，可通过D-前列腺素受体1（DP1）抑制1型T辅助（Th1）细胞因子。本研究旨在探讨前列腺素D ₂ / DP1轴在T细胞中与年龄相关性高血压的作用。年轻人和年长的男性参与者，以及CD4 ⁺将T细胞分类以进行基因表达，前列腺素产生和Western印迹测定。结果：通过老年人和老年小鼠的CD4 ⁺ T细胞，前列腺素D ₂ / DP1轴被下调。CD4 ⁺ T细胞中的DP1缺失通过增强Th1细胞因子分泌，血管重塑，CD4 ⁺T细胞浸润以及血管和肾脏中的超氧化物产生。相反，T细胞中外源DP1的强制表达通过减少Th1细胞因子的分泌来延缓小鼠的年龄相关性高血压。肿瘤坏死因子α中和或干扰素γ的缺失改善了CD4 ⁺ T细胞小鼠DP1缺失中与年龄有关的高血压。从机制上讲，DP1通过PKA（蛋白激酶A）/ p-Sp1（磷酸化特异性蛋白1）/神经前体细胞抑制Th1的活性，该神经前体细胞通过发育性下调的4样（NEDD4L）途径介导的T-box-in-T-表达细胞（T-bet）泛素化。CD4 ⁺ T细胞中的T-bet缺失或NEDD4L的强制表达减弱了CD4 ^+中与年龄有关的高血压T细胞特异性DP1缺陷小鼠。BW245C激活DP1受体可防止雄性小鼠出现与年龄相关的血压升高，并减少血管/肾脏超氧化物的产生。结论：前列腺素D ₂ / DP1轴可通过增加NEDD4L抑制雄性小鼠中与年龄相关的Th1激活和随后的高血压反应。介导的泛素降解。因此，T细胞DP1受体可能是与年龄有关的高血压的有吸引力的治疗靶标。