CD4+ T-Cell Endogenous Cystathionine γ Lyase-Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation.

ABSTRACT

BACKGROUND: Hydrogen sulfide (H2S) has antihypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4+ T cells. However, the role of CD4+ T-cell endogenous CSE/H2S in the development of hypertension is unclear. METHODS: Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats, then H2S production and expression of its generation enzymes, cystathionine ß synthase and CSE, were measured to determine the major H2S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (conditional knockout, by CD4cre mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/H2S system. RESULTS: In lymphocytes, H2S from CSE, but not cystathionine ß synthase, responded to blood pressure changes, supported by lymphocyte CSE protein changes and a negative correlation between H2S production with systolic blood pressure and diastolic blood pressure, but positive correlation with the serum level of interleukin 10 (an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mm Hg) under the physiological condition and exacerbated angiotensin II-induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in the blood and kidney, thus causing excess CD4+ and CD8+ T cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4+ T cell transfer into CD4 null mice, also showed the similar phenotypes' confirming the role of endogenous CSE/H2S action. Adoptive transfer of Tregs (to conditional knockout mice) reversed hypertension, vascular relaxation impairment, and immunocyte infiltration, which confirmed that conditional knockout-induced hypertension was attributable, in part, to the reduced Treg numbers. Mechanistically, endogenous CSE/H2S promoted Treg differentiation and proliferation by activating AMP-activated protein kinase. In part, it depended on activation of its upstream kinase, liver kinase B1, by sulfhydration to facilitate its substrate binding and phosphorylation. CONCLUSION: The constitutive sulfhydration of liver kinase B1 by CSE-derived H2S activates its target kinase, AMP-activated protein kinase, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.