Paradoxical attenuation of dyslipidemia and atherosclerosis in Apoe-/-Mpst-/- mice.

Hydrogen sulfide (H2S) is a signaling molecule that affects multiple (patho)physiological pathways. Deficiency of H2S due to cystathionine γ-lyase (CSE) deletion has been proven to accelerate atherosclerotic plaque formation. However, the role of 3-mercaptopyruvate sulfurtransferase (MPST), a related H2S-producing enzyme that impacts metabolism, has not been studied in atherogenic dyslipidemia. We generated a double Apoe/Mpst knockout mouse (Apoe-/-Mpst-/-) in the C57BL/6 background. C57Bl/6, Mpst-/-, Apoe-/- and Apoe-/-Mpst-/-mice were fed a western diet for 14 weeks, after which blood and tissues (aorta and liver) were collected; the circulating lipid profile, atherosclerotic plaque formation and expression of enzymes involved in lipid biosynthetic pathways in the liver were evaluated in the four mouse lines. H2S production was reduced in the liver of double knockout mice, while the expression of CBS and CSE was not altered. In the serum of Apoe-/-Mpst-/-, we observed decreased levels of total cholesterol, low-density lipoproteins (LDL) and triglycerides (TGs) compared to Apoe-/-; hepatic apolipoprotein B (ApoB) levels were also downregulated. However, the expression of other key enzymes that participate in cholesterol and fatty acid synthesis remained unchanged. In addition, hepatic lipid deposition was not significantly altered among genotypes. In line with the reduced circulating LDL and TGs levels, atherosclerotic lesions were found to be reduced in the aorta of Apoe-/-Mpst-/-. Our results indicate that MPST deletion in the Apoe-/- dyslipidemia model leads to decreased circulating lipid levels and atherosclerosis, that correlate with a downregulation of hepatic ApoB expression.