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 (H 2 S) 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/H 2 S in the development of hypertension is unclear. Methods: Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats (SHRs), then H 2 S production and expression of its generation enzymes, cystathionine β synthase (CBS) and CSE, were measured to determine the major H 2 S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (CKO, by CD4 cre mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/H 2 S system. Results: In lymphocytes, H 2 S from CSE but not CBS responded to blood pressure (BP) changes, supported by lymphocyte CSE protein changes and negative correlation between H 2 S 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/H 2 S 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/H 2 S 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 H 2 S activates its target kinase, AMPK, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.

Emerging roles of cystathionine β-synthase in various forms of cancer

“…The mechanism by which H 2 S stimulates AMPK phosphorylation may be related, at least in part, to the sulfhydration of liver kinase B1 (LKB1) leading to phosphorylation at Ser428 and/or to the activation of calcium/calmodulin-activated protein kinase 2 (CaMKK2) ( Fig. 10 , Pathway #3) [ 303 , 304 ]. The body of information regarding the capacity of endogenous H 2 S to regulate these pathways in cancer cells remains to be further investigated.…”

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

“…These data would then suggest that metformin could instead repress an antitumorigenic phenotype in T cells if its action was through the induction of LKB1 activity. In contrast, the activation of LKB1 and downstream AMPK activity have been shown to promote the infiltration of CD8 + T cells into perivascular adipose depots in vivo in a murine model of hypertension [36]; whether this may apply to the adipocyte-rich omentum and peritoneum in the context of ovarian cancer metastasis has yet to be determined and remains an important mechanism to elucidate.…”

Endogenous hydrogen sulfide regulates xCT stability through persulfidation of OTUB1 at cysteine 91 in colon cancer cells

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