L-cysteine and hydrogen sulfide increase PIP3 and AMPK/PPARγ expression and decrease ROS and vascular inflammation markers in high glucose treated human U937 monocytes

Abstract

Diabetic patients have lower blood levels of L‐cysteine (LC) and hydrogen sulfide (H2S) and a higher incidence of vascular inflammation. This study examined whether impaired LC or H2S levels affect vascular inflammation markers in diabetes. Human U937 monocytic cells were treated with high‐glucose (HG, 25 mM, 20 h) in the presence or absence of LC (100, 500, or 1,000 µM, an endogenous precursor of H2S) or Na2S (5 or 25 µM, an exogenous source of H2S). Both LC and Na2S supplementation decreased intracellular ROS production and increased cellular PIP3 (phosphatidylinositol‐3,4,5‐trisphosphate) in HG‐exposed cells. The effect of LC on PIP3 was prevented by propargylglycine, an inhibitor of cystathionine‐γ‐lyase (CSE) that catalyzes H2S formation from LC. Signal silencing studies with CSE siRNA also showed the inhibition of H2S formation and PIP3 upregulation in LC‐supplemented CSE knockdown cells exposed to HG. This demonstrates that H2S plays a role in mediating the effect of LC on increased PIP3. Using the PI3K specific inhibitor LY294002, this study demonstrated that PI3K activation mediates the effect of LC and Na2S on PIP3 upregulation. Results showed that supplementation with LC and Na2S reduced NF‐κB phosphorylation and the secretion of TNF‐α, MCP‐1, IL‐8, IL‐1β, and IP‐10. Treatment with LC (500 µM), Na2S (25 µM), and PIP3 (5 nM) increased the AMPK phosphorylation and PPARγ expression in cells exposed to HG. This study reports for the first time a novel molecular mechanism by which Na2S or LC supplementation can lower oxidative stress and various markers of vascular inflammation in diabetes. J. Cell. Biochem. 114: 2334–2345, 2013. © 2013 Wiley Periodicals, Inc.

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

“…H 2 S has also been shown to have powerful antioxidant properties. Exogenous H 2 S attenuates the hyperglycemia-induced enhancement of ROS formation in endothelial cells and human U937 monocytes (8,28). In line with these findings, we observed that H 2 S decreased superoxide generation in macrophages and endothelial cells cultured with HG+ox-LDL.…”

Decreased Cystathionine-γ-lyase (CSE) Activity in Livers of Type 1 Diabetic Rats and Peripheral Blood Mononuclear Cells (PBMC) of Type 1 Diabetic Patients

“…Fig. 9 demonstrates that exogenous supplementation with 1,25-dihydroxyvitamin D 3 , an active form of vitamin D, up-regulates both CSE protein expression and its activity as well as H 2 S levels in PBMC treated with either HG alone or in combination with AA, suggesting a positive effect of vitamin D on H 2 S homeostasis in diabetes.…”

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

“…This indicates that the signaling and effector pathways downstream from H 2 S are not impaired significantly in experimental models used in the current study. It must be noted that, depending on the experimental conditions and models used, the other H 2 S-producing enzyme systems also have been shown to be affected by diabetes and diabetic complications (8)(9)(10)(11)(12)(13)(14)(15)(65)(66)(67); overviewed in [67]). Thus, it is likely that there is a complex dysregulation of the H 2 S system in diabetes, the nature of which depends on the model used, as well as the stage and severity of the disease.…”

“…It exerts protective effects against hyperglycemic stress in the vascular endothelium and exhibits protective effects in animal models of diabetic complications (8)(9)(10)(11)(12)(13)(14)(15)(16).…”