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

Background: Hydrogen sulfide (H2S) has anti-hypertension 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 (SHRs), then H2S production and expression of its generation enzymes, cystathionine β synthase (CBS) and CSE, were measured to determine the major H2S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (CKO, 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 CBS responded to blood pressure (BP) changes, supported by lymphocyte CSE protein changes and negative correlation between H2S production with systolic BP (sBP) and diastolic BP (dBP) but positive correlation with serum level of interleukin 10 (IL-10, an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mmHg) under the physiological condition and exacerbated angiotensin II (AngII)-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 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 CKO mice) reversed hypertension, vascular relaxation impairment and immunocyte infiltration, which confirmed that CKO-induced hypertension was due in part to the reduced Treg numbers. Mechanistically, endogenous CSE/H2S promoted Treg differentiation and proliferation by activating AMP-activated protein kinase (AMPK). In part, it depended on activation of its upstream kinase, liver kinase B1 (LKB1), by sulfhydration to facilitate its substrate binding and phosphorylation. Conclusions: The constitutive sulfhydration of LKB1 by CSE-derived H2S activates its target kinase, AMPK, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.