DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells

作者：Deping Kong, Qiangyou Wan, Juanjuan Li, Shengkai Zuo, Guizhu Liu, Qian Liu, Chenchen Wang, Peiyuan Bai, Sheng‐Zhong Duan, Bin Zhou, Fotini Gounari, Ankang Lyu, Michael Lazarus, Richard Breyer, Ying Yu · 发表于：Circulation · 年份：2020 · DOI：10.1161/circulationaha.119.042532 · 被引用次数：44 · 研究领域：Sodium Intake and Health、Hormonal Regulation and Hypertension、Apelin-related biomedical research

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 spe...