Hydrogen sulfide inhibits macrophage-derived foam cell formation

Abstract

Recent evidence indicates that hydrogen sulfide (H(2)S) exerts an antiatherogenic effect, but the mechanism is unclear. Formation of macrophage-derived foam cells is a crucial event in the development of atherosclerosis. Thus, we explore the effect of H(2)S on the formation of macrophage-derived foam cells. Incubation of monocyte-derived macrophages with oxidized LDL (oxLDL) alone caused significant increases both in intracellular lipids revealed by Oil-red O staining and in intracellular total cholesterol (TC) and esterified cholesterol (EC) concentrations assessed by high-performance liquid chromatography. Sodium hydrosulfide (NaHS, an H(2)S donor) remarkably abrogated oxLDL-induced intracellular lipid accumulation, and attenuated TC and EC concentrations and EC/TC ratio, whereas dl-propargylglycine (PPG) (a H(2)S-generating enzyme cystathionine gamma lyase inhibitor) exacerbated lipid accumulation and augmented TC and EC concentrations and EC/TC ratio. Incubation of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-oxLDL led to lipoprotein binding and uptake of macrophages, which was blunted by NaHS, but enhanced by PPG. Furthermore, OxLDL markedly induced CD36, scavenger receptor A (SR-A) and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) expressions in macrophages, which was suppressed by NaHS (50-200 μmol/L). Finally, the down-regulations of TC and EC concentrations as well as CD36 and ACAT-1 expressions by NaHS were suppressed by glibenclamide, a K(ATP) channel blocker, but facilitated by PD98059, an extracellular signal-regulated kinases 1 and 2 (ERK1/2) inhibitor. These results suggested that H(2)S inhibits foam cell formation by down-regulating CD36, SR-A and ACAT1 expressions via the K(ATP)/ERK1/2 pathway in human monocyte-derived macrophages.

Hydrogen Sulfide Suppresses Oxidized Low-density Lipoprotein (Ox-LDL)-stimulated Monocyte Chemoattractant Protein 1 generation from Macrophages via the Nuclear Factor κB (NF-κB) Pathway

“…Previous studies have demonstrated that H 2 S can inhibit macrophage-derived foam cell formation (16,(25)(26). Our research group confirmed that H 2 S generation in vessels was decreased in apoE Ϫ/Ϫ mice and that it was an important factor in the formation and development of atherosclerosis (16).…”

Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

“…For instance, H 2 S plays an antiatherogenic role by suppressing the formation of human macrophage foam cells. H 2 S inhibits the formation of macrophage-derived foam cells, which is a crucial event in the development of atherosclerosis, by downregulating CD36, SR-A, and ACAT-1 expression and inhibiting oxidized low-density lipoprotein (oxLDL) binding and uptake of macrophages (66,67). In addition to its important role in preventing atherosclerosis, H 2 S has also direct benefits for coronary heart disease (CHD) patients.…”

Interferon-γ: Promising therapeutic target in atherosclerosis

“…Other therapies target IFN-γ via alternative signaling pathways, for example, ACS14 (a hydrogen sulphide releasing aspirin) is capable of attenuating the expression of IFN-γ-stimulated CX3 chemokine receptor 1 (CX3CR1) via a peroxisome proliferator-activated receptor-γ-dependent mechanism [48] . Hydrogen sulphide has previously been shown to exert anti-atherogenic effects and its use in ACS14 has been shown to reduce atherosclerosis development in ApoE mice models [48,49] . IFN-γ neutralization involves the use of a soluble IFN-γR (sIFN-γR) which acts as decoy receptor to prevent the activation of IFN-γR and in turn the phosphorylation of STAT1 in the JAK-STAT pathway, in effect "neutralizing" the IFN-γ.…”