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Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine γ lyase S-sulfhydration in ApoE-knockout atherosclerotic mice.
- Source :
-
British Journal of Pharmacology . Sep2019, Vol. 176 Issue 17, p3180-3192. 13p. 1 Diagram, 6 Graphs. - Publication Year :
- 2019
-
Abstract
- <bold>Background and Purpose: </bold>Hydrogen sulfide donors can block the cardiovascular injury of hyperhomocysteinemia. H2 S also lowers serum homocysteine in rats with mild hyperhomocysteinemia, but the pharmacological mechanism is unknown. The present study investigated the mechanism(s) involved.<bold>Experimental Approach: </bold>ApoE-knockout mice were fed a Paigen diet and L-methionine in drinking water for 16 weeks to create a mouse model of atherosclerosis with hyperhomocysteinemia. H2 S donors (NaHS and GYY4137) were administered by intraperitoneal injection. We also assayed the H2 S produced (by methylene blue assay and mito-HS [H2 S fluorescence probe]), cystathionine γ lyase (CSE) mRNA and protein expression, and CSE sulfhydration and nitrosylation and its activity.<bold>Key Results: </bold>H2 S donor treatment significantly lowered atherosclerotic plaque area, macrophage infiltration, and serum homocysteine level in the mouse model of atherosclerosis with co-existing hyperhomocysteinemia. mRNA and protein levels of CSE, a key enzyme catalyzing homocysteine trans-sulfuration, were down-regulated with hyperhomocysteinemia, and CSE catalytic activity was inhibited. All these effects were reversed with H2 S donor treatment. Hyperhomocysteinemia induced CSE nitrosylation, whereas H2 S sulfhydrated CSE at the same cysteine residues. Nitrosylated CSE decreased and sulfhydrated CSE increased its catalytic and binding activities towards L-homocysteine. Mutation of C252, C255, C307, and C310 residues in CSE abolished CSE nitrosylation or sulfhydration and prevented its binding to L-homocysteine.<bold>Conclusions and Implications: </bold>Sulfhydration or nitrosylation of CSE represents a yin/yang regulation of catalysis or binding to L-homocysteine. H2 S donor treatment enhanced CSE sulfhydration, thus lowering serum L-homocysteine, which contributed in part to the anti-atherosclerosis effects in ApoE-knockout mice with hyperhomocysteinemia. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 176
- Issue :
- 17
- Database :
- Academic Search Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 138089032
- Full Text :
- https://doi.org/10.1111/bph.14719