Hydrogen Sulfide Inhibits Abnormal Proliferation of Lymphocytes via AKT/GSK3� Signal Pathway in Systemic Lupus Erythematosus Patients

Abstract

Background/Aim: The abnormal activation of the AKT/GSK3β signal pathway in lymphocytes from systemic lupus erythematosus (SLE) patients plays an important role in the pathogenesis of the disease. Recently Hydrogen sulfide (H₂S) has been recognized as a crucial gaseous signaling molecule, involved in regulation of cell proliferation. However, the role of H₂S in regulating the abnormal activation of lymphocytes from SLE patients has not been established. This study was conducted to investigate the effect of H₂S on lymphocytes and to explore the mechanisms involved. Methods: The lymphocytes were isolated from SLE patients with or without renal disease and healthy controls. The cells were treated as indicated in each experiment. Cell viability was analyzed by CCK-8. Cell cycle distribution was determined by flow cytometry. Western blot was used to detect the expression of phosphorylated AKT (ser473), GSK3β (ser9) and CDK2, p27^Kip1 and p21^WAF1/CIP1. Results: Our findings showed that proliferation of lymphocytes was stimulated following treatment with NaHS (a H₂S donor) at low NaHS concentrations (<1mM) but inhibited at high NaHS concentrations (>2mM). Similar results were observed using GYY4137, which is a slow-releasing H₂S donor. Pretreatment of lymphocytes from SLE patients with NaHS at high concentrations prior to exposure to phytohemagglutinin (PHA) significantly attenuated proliferation, evidenced by decrease in cell viability and S phase distribution of cell cycle. Pretreatment with NaHS decreased PHA-induced expression of CDK2, phosphorylation levels of AKT (ser473) and GSK3β (ser9) and increased the expression of p27^Kip1 and p21^WAF1/CIP1. Moreover, pretreatment with NaHS blunted the stimulation of SLE lymphocyte proliferation by GSK3β inhibitor lithium chloride. Conclusion: These results demonstrate that H₂S inhibits the abnormal activation of lymphocytes from SLE patients throuqh the AKT/GSK3β signal pathway.

Exogenous Hydrogen Sulfide Attenuates Cardiac Fibrosis Through Reactive Oxygen Species Signal Pathways in Experimental Diabetes Mellitus Models

“…H 2 S decreased the expression of the P47 NADPH oxidase subunit, which is related to oxidative stress stimulation via the NF-κB pathway. Some studies demonstrated that treatment with exogenous H 2 S suppresses the expression of pro-fibrotic genes fibronectin and galectin-3 mRNA levels, and the expression of fibrotic marker CTGF in AngII-stimulated cardiac fibroblasts [14,41,42]. Our previous studies have shown that NaHS (a H 2 S donor) was potent at inhibiting NOX4 expression and activity under oxidative stress conditions.…”

Hydrogen Sulfide Attenuates Myocardial Hypoxia-Reoxygenation Injury by Inhibiting Autophagy via mTOR Activation

“…Recently, H 2 S, a gasotransmitter, has attracted wide attention because of its protective effect of brain, liver, kidney, heart, lung and other organs [20][21][22][23][24]. Many studies have demonstrated the cytoprotective effects of H 2 S in myocardial IR injury [25,26].…”

ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

“…Recently in a rat model, H 2 S was reported to protect cardiomyoblasts against oxidative challenge through the inhibition of L-type calcium channels [6]. More importantly in systemic lupus erythematosus patients, H 2 S was found to inhibit the abnormal activation of lymphocytes through the AKT/GSK3β signal pathway [7]. Moreover, an N-mercapto-based H 2 S donor was recently found to protect human skin keratinocytes against methylglyoxalinduced injury and behavior dysfunction [8].…”