S-EPMC6692586 - Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine γ lyase S-sulfhydration in ApoE-knockout atherosclerotic mice. - OmicsDI

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Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine γ lyase S-sulfhydration in ApoE-knockout atherosclerotic mice.

ABSTRACT:

Background and purpose

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.

Experimental approach

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.

Key results

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.

Conclusions and implications

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.

SUBMITTER: Fan J

PROVIDER: S-EPMC6692586 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine γ lyase S-sulfhydration in ApoE-knockout atherosclerotic mice.

Fan Jinhui J Zheng Fengjiao F Li Shuangyue S Cui Cangting C Jiang Shan S Zhang Jun J Cai Jun J Cui Qinghua Q Yang Jichun J Tang Xinjing X Xu Guoheng G Geng Bin B

British journal of pharmacology 20190714 17

<h4>Background and purpose</h4>Hydrogen sulfide donors can block the cardiovascular injury of hyperhomocysteinemia. H<sub>2</sub> S also lowers serum homocysteine in rats with mild hyperhomocysteinemia, but the pharmacological mechanism is unknown. The present study investigated the mechanism(s) involved.<h4>Experimental approach</h4>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. H<su ...[more]

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