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 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.

The efficacy of antiplatelet therapies as evaluated by thrombo-elastography in retired Chinese officers.

AIM: This study evaluated, using thrombo-elastography (TEG), the efficacy of antiplatelet therapies in retired Chinese officers and explored the factors influencing the efficacy of antiplatelet therapies. METHODS: Nine hundred and fifty-five retired male Chinese officers (≥ 60 years old), who had undergone TEG between June and August 2015 at the Chinese People's Liberation Army General Hospital (PLAGH), were enrolled in this study. The subjects were divided into four groups according to the antiplatelet drug(s) that they were administered: aspirin, clopidogrel, dual drugs (combination of aspirin and clopidogrel) and no antiplatelet drug. TEG was used to evaluate the efficacy of antiplatelet therapy in the four groups. RESULTS: The inhibition of platelet aggregation induced by arachidonic acid (AA%) was 48.0 ± 19.3% in the aspirin group, and the inhibition induced by adenosine diphosphate (ADP%) was 63.0 ± 18.2% in the clopidogrel group. The AA% and ADP% in the dual-drug group were 51.0 ± 16.5 and 46.0 ± 15.3%, respectively. The total efficacy of antiplatelet therapy was 45.9% in the aspirin group, 51.2% in the clopidogrel group and 81.4% in the dual-drug group. A multivariate logistic regression analysis of the maximum amplitude of ADP-induced platelet-fibrin clot strength (MA-ADP) indicated that in the population with MA-ADP < 31 mm, an increased white blood cell count (OR = 1.262, p < 0.001) was a risk factor, while an increased platelet count (OR = 0.995, p = 0.013) was a protective factor for bleeding. In the population with MA-ADP > 47 mm, increased platelet count (OR = 1.006, p < 0.001), estimated glomerular filtration rate (eGFR, OR = 1.016, p = 0.013) and glycated haemoglobin levels (HbA1c, OR = 1.358, p = 0.011) were risk factors for thrombosis. CONCLUSIONS: This quality-controlled TEG procedure was an efficient method to evaluate the efficacy of antiplatelet therapies in the clinic. White blood cell and platelet counts, and eGFR and HbA1c levels may influence the efficacy of an antiplatelet therapy.

Reduction of leukocyte-derived H2S linked to abnormal glycolipid metabolism in hypertensive subjects.

We deduced that leukocyte-derived H2S would also play a pivotal role regarding nutrition homeostasis in hypertensive subjects. Plasma was obtained from patients with hypertension (n = 151) as well as control (n = 41). Leukocyte-derived H2S speed was determined, and biochemical indices of glucose and lipid metabolism were measured. Western blot analyses of CSE were also performed. Inflammation factors were measured. Leukocyte-derived H2S is produced at a significantly lower rate in overweight or obese patients (p < 0.05). There is a significant negative correlation between H2S and the levels of HOMA-RI and insulin in overweight patients and has a positive relationship with HDL-C only in overweight hypertensive patients (p < 0.05). Patients with high insulin levels showed down-regulation of CSE (p < 0.05). The levels of IL-10 decreased in both the obese and the overweight which showed significant relationship with all metabolism parameters such as HDL-C(r = 0.176, p = 0.031), insulin (r = -0.181, p = 0.027), HOMA-IR (r = -0.166, p = 0.045), and H2S speed (r = 0.995, p = 0.001). Linear regression analysis showed that insulin levels will increase (ß = -1.685, p = 0.041) with the slower speed of H2S. Leukocyte-derived H2S production varied according to the nutritional status of hypertensive subjects, and the H2S/IL-10 signaling pathway may be the junction point among hypertension, disturbance of nutritional status, and inflammation.