Dysregulation of cystathionine γ-lyase (CSE)/hydrogen sulfide pathway contributes to ox-LDL-induced inflammation in macrophage

Cell Signal. 2013 Nov;25(11):2255-62. doi: 10.1016/j.cellsig.2013.07.010. Epub 2013 Jul 18.


Hydrogen sulfide (H2S), mainly produced by cystathionine γ-lyase (CSE) in vascular system, emerges as a novel gasotransmitter exerting anti-inflammatory and anti-atherosclerotic effects. Alterations of CSE/H2S pathway may thus be involved in atherosclerosis pathogenesis. However, the underlying mechanisms are poorly understood. The present study showed that the levels of CSE mRNA and protein expression, as well as H2S production were decreased in ox-LDL-treated macrophage. CSE overexpression reduced the ox-LDL-stimulated tumor necrosis factor-α (TNF-α) generation in Raw264.7 and primary macrophage while CSE knockdown enhanced it. Exogenous supplementation of H2S with NaHS and Na2S also decreased the production of TNF-α and intercellular adhesion molecule-1 (ICAM-1) in ox-LDL-stimulated macrophage, and alleviated the adhesion of macrophage to endothelial monolayer. Cysteine, a CSE preferential substrate for H2S biosynthesis, produced similar effects on the pro-inflammatory cytokine generation, which were reversed by CSE inhibitors PAG and BCA, respectively. Moreover, NaHS and Na2S attenuated the phosphorylation and degradation of IκBα and p65 nuclear translocation, as well as JNK activation caused by ox-LDL. The JNK inhibitor suppressed the NF-κB transcription activity in ox-LDL-treated cells. Furthermore, inhibitors of NF-κB (PDTC), ERK (U0126 and PD98059) and JNK (SP600125) partially blocked the suppression by ox-LDL on the CSE mRNA levels. Taken together, the findings demonstrate that ox-LDL may down-regulate the CSE/H2S pathway, which plays an anti-inflammatory role in ox-LDL-stimulated macrophage by suppressing JNK/NF-κB signaling. The study reveals new therapeutic strategies for atherosclerosis, based on modulating CSE/H2S pathway.

Keywords: ApoE; BCA; CBS; CSE; Cystathionine-γ-lyase; H(2)S; HUVEC; Hydrogen sulfide; ICAM-1; Inflammation; JNK; LDL; Macrophage; Oxidized-LDL; PAG; SMC; TNF-α; apolipoprotein E; cystathionine γ-lyase; cystathionine-β-synthase; dl-propargylglycine; human umbilical vein endothelial cells; hydrogen sulfide; intercellular adhesion molecule-1; low-density lipoprotein; ox-LDL; oxidized LDL; smooth muscle cell; tumor necrosis factor-α; β-cyano-l-alanine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / drug effects
  • Cell Line
  • Cystathionine gamma-Lyase / antagonists & inhibitors
  • Cystathionine gamma-Lyase / genetics*
  • Cystathionine gamma-Lyase / metabolism
  • Cysteine / metabolism
  • Cysteine / pharmacology
  • Gene Expression Regulation
  • Guanidines / pharmacology
  • Hydrogen Sulfide / metabolism*
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / metabolism
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipoproteins, LDL / pharmacology*
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • Primary Cell Culture
  • Pyridoxal / pharmacology
  • Signal Transduction / drug effects*
  • Sulfhydryl Compounds / pharmacology
  • Sulfides / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • 6,6-dimethyl-4-(2-(2,2-dimethyl-2-(2-methyl-2-thiopropyl)amino)ethyl)thiamorpholin-2-one
  • Guanidines
  • I-kappa B Proteins
  • Lipoproteins, LDL
  • Morpholines
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Sulfhydryl Compounds
  • Sulfides
  • Tumor Necrosis Factor-alpha
  • oxidized low density lipoprotein
  • pyridoxylidene aminoguanidine
  • Intercellular Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha
  • Pyridoxal
  • JNK Mitogen-Activated Protein Kinases
  • Cystathionine gamma-Lyase
  • sodium bisulfide
  • Cysteine
  • Hydrogen Sulfide