期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2212476120
关键词
acetylcholine; lymphocytes; circulation; vascular biology
Endothelial dysfunction and impaired vasodilation are associated with adverse cardiovascular events. T lymphocytes expressing ChAT regulate vasodilation and play a role in the cholinergic antiinflammatory pathway. ChAT mRNA expression in human T cells is induced through the PI3K signaling cascade and regulated by REST-mediated methylation and up-regulation by GATA3. Functional experiments demonstrate that T cell-derived ACh promotes endothelial nitric oxide-synthase activity, vasorelaxation, and barrier integrity. Additionally, the frequency of ChAT(+)CD4(+) T cells in blood correlates with survival in patients with severe circulatory failure. These findings provide a mechanism for cholinergic immune regulation of vascular endothelial function in human inflammation.
Endothelial dysfunction and impaired vasodilation are linked with adverse cardiovascular events. T lymphocytes expressing choline acetyltransferase (ChAT), the enzyme catalyzing biosynthesis of the vasorelaxant acetylcholine ( ACh), regulate vasodilation and are integral to the cholinergic antiinflammatory pathway in an inflammatory reflex in mice. Here, we found that human T cell ChAT mRNA expression was induced by T cell activation involving the PI3K signaling cascade. Mechanistically, we identified that ChAT mRNA expression was induced following the attenuation of RE-1 Silencing Transcription factor REST-mediated methylation of the ChAT promoter, and that ChAT mRNA expression levels were up-regulated by GATA3 in human T cells. In functional experiments, T cell- derived ACh increased endothelial nitric oxide-synthase activity, promoted vasorelaxation, and reduced vascular endothelial activation and promoted barrier integrity by a cholinergic mechanism. Further, we observed that survival in a cohort of patients with severe circulatory failure correlated with their relative frequency of ChAT(+)CD4(+) T cells in blood. These findings on ChAT(+) human T cells provide a mechanism for cholinergic immune regulation of vascular endothelial function in human inflammation.
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