Document Detail

Cystathionine β-synthase and cystathionine γ-lyase double gene transfer ameliorate homocysteine-mediated mesangial inflammation through hydrogen sulfide generation.
MedLine Citation:
PMID:  20943958     Owner:  NLM     Status:  MEDLINE    
Elevated level of homocysteine (Hcy) induces chronic inflammation in vascular bed, including glomerulus, and promotes glomerulosclerosis. In this study we investigated in vitro mechanism of Hcy-mediated monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) induction and determined the regulatory role of hydrogen sulfide (H₂S) to ameliorate inflammation. Mouse glomerular mesangial cells (MCs) were incubated with Hcy (75 μM) and supplemented with vehicle or with H₂S (30 μM, in the form of NaHS). Inflammatory molecules MCP-1 and MIP-2 were measured by ELISA. Cellular capability to generate H₂S was measured by colorimetric chemical method. To enhance endogenous production of H₂S and better clearance of Hcy, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) genes were delivered to the cells. Oxidative NAD(P)H p47(phox) was measured by Western blot analysis and immunostaining. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH₂-terminal kinase (JNK1/2) were measured by Western blot analysis. Our results demonstrated that Hcy upregulated inflammatory molecules MCP-1 and MIP-2, whereas endogenous production of H₂S was attenuated. H₂S treatment as well as CBS and CSE doubly cDNA overexpression markedly reduced Hcy-induced upregulation of MCP-1 and MIP-2. Hcy-induced upregulation of oxidative p47(phox) was attenuated by H₂S supplementation and CBS/CSE overexpression as well. In addition to that we also detected Hcy-induced MCP-1 and MIP-2 induction was through phosphorylation of ERK1/2 and JNK1/2. Either H₂S supplementation or CBS and CSE doubly cDNA overexpression attenuated Hcy-induced phosphorylation of these two signaling molecules and diminished MCP-1 and MIP-2 expressions. Similar results were obtained by inhibition of ERK1/2 and JNK1/2 using pharmacological and small interferring RNA (siRNA) blockers. We conclude that H₂S plays a regulatory role in Hcy-induced mesangial inflammation and that ERK1/2 and JNK1/2 are two signaling pathways involved this process.
Utpal Sen; Srikanth Givvimani; Oluwasegun A Abe; Eleanor D Lederer; Suresh C Tyagi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-10-13
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  300     ISSN:  1522-1563     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-29     Completed Date:  2011-02-04     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C155-63     Citation Subset:  IM    
Department of Physiology & Biophysics, University of Louisville, KY 40202, USA.
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MeSH Terms
Cells, Cultured
Chemokine CCL2 / genetics,  metabolism
Chemokine CXCL2 / genetics,  metabolism
Cystathionine beta-Synthase / genetics,  metabolism*
Cystathionine gamma-Lyase / genetics,  metabolism*
Extracellular Signal-Regulated MAP Kinases / genetics,  metabolism
Gene Expression Regulation / physiology
Homocysteine / metabolism*
Hydrogen Sulfide / metabolism*
Inflammation / metabolism,  pathology*
JNK Mitogen-Activated Protein Kinases / genetics,  metabolism
Mesangial Cells / metabolism*
Signal Transduction / physiology
Grant Support
Reg. No./Substance:
0/Ccl2 protein, mouse; 0/Chemokine CCL2; 0/Chemokine CXCL2; 0/Cxcl2 protein, mouse; 454-28-4/Homocysteine; 7783-06-4/Hydrogen Sulfide; EC Signal-Regulated MAP Kinases; EC Mitogen-Activated Protein Kinases; EC beta-Synthase; EC gamma-Lyase

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