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

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.

• Authors: 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 M Breyer, Ying Yu
• Journal: Circulation (Circulation) Vol. 141 Issue 8 Pg. 655-666 (02 25 2020) ISSN: 1524-4539 [Electronic] United States
• PMID: 31893939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Cytokines
• Receptors, Prostaglandin
• Sp1 Transcription Factor
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Superoxides
• Nedd4 Ubiquitin Protein Ligases
• Nedd4l protein, mouse
• Cyclic AMP-Dependent Protein Kinases
• Prostaglandin D2

Topics

• Aged
• Aging
• Animals
• Antihypertensive Agents (therapeutic use)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Cytokines (metabolism)
• Humans
• Hypertension (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Nedd4 Ubiquitin Protein Ligases (metabolism)
• Prostaglandin D2 (metabolism)
• Receptors, Prostaglandin (agonists, deficiency, genetics, metabolism)
• Signal Transduction
• Sp1 Transcription Factor (metabolism)
• Superoxides (metabolism)
• T-Box Domain Proteins (metabolism)
• Th1 Cells (metabolism)
• Ubiquitination