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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
Author(s) -
Manna Prasenjit,
Jain Sushil K.
Publication year - 2013
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.24578
Subject(s) - downregulation and upregulation , ampk , chemistry , inflammation , pi3k/akt/mtor pathway , cystathionine beta synthase , ly294002 , endocrinology , medicine , phosphorylation , signal transduction , cysteine , biochemistry , biology , protein kinase a , enzyme , gene
Abstract Diabetic patients have lower blood levels of L ‐cysteine (LC) and hydrogen sulfide (H 2 S) and a higher incidence of vascular inflammation. This study examined whether impaired LC or H 2 S 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 H 2 S) or Na 2 S (5 or 25 µM, an exogenous source of H 2 S). Both LC and Na 2 S 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 H 2 S formation from LC. Signal silencing studies with CSE siRNA also showed the inhibition of H 2 S formation and PIP3 upregulation in LC‐supplemented CSE knockdown cells exposed to HG. This demonstrates that H 2 S 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 Na 2 S on PIP3 upregulation. Results showed that supplementation with LC and Na 2 S reduced NF‐κB phosphorylation and the secretion of TNF‐α, MCP‐1, IL‐8, IL‐1β, and IP‐10. Treatment with LC (500 µM), Na 2 S (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 Na 2 S 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.