The hydrogen sulfide donor, GYY4137, exhibits anti‐atherosclerotic activity in high fat fed apolipoprotein E−/− mice

Background and PurposeAtherosclerosis is associated with reduced vascular hydrogen sulfide (H2S) biosynthesis. GYY4137 is a novel slow‐releasing H2S compound that may effectively mimic the time course of H2S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis.Experimental ApproachRAW 264.7 cells and human blood monocyte‐derived macrophages were incubated with oxidized low density lipoprotein (ox‐LDL) with/without GYY4137. ApoE−/− mice were fed a high‐fat diet for 4 weeks and administered GYY4137 for 30 days. Lipid and atherosclerotic lesions were measured by oil red O staining. Endothelium‐dependent relaxation was assessed in response to acetylcholine. Superoxide production was detected by dihydroethidium staining. Expression of mRNA and protein were evaluated by quantitative real‐time PCR and Western blot.Key ResultsGYY4137 inhibited ox‐LDL‐induced foam cell formation and cholesterol esterification in cultured cells. GYY4137 decreased the expression of lectin‐like ox‐LDL receptor‐1, iNOS, phosphorylated IκBα, NF‐κB, ICAM‐1, VCAM‐1 and chemokines, including CXCL2, CXCR4, CXCL10 and CCL17, but increased the scavenger protein CD36, in ox‐LDL‐treated RAW 264.7 cells. In vivo, GYY4137 decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium‐dependent relaxation in apoE−/− mice. GYY4137 decreased ICAM‐1, TNF‐α and IL‐6 mRNA expression as well as superoxide (O2−) generation in aorta. In addition, GYY4137 increased aortic eNOS phosphorylation and expression of PI3K, enhanced Akt Ser473 phosphorylation and down‐regulated the expression of LOX‐1.Conclusion and ImplicationsGYY4137 inhibits lipid accumulation induced by ox‐LDL in RAW 264.7 cells. In vivo, GYY4137 decreased vascular inflammation and oxidative stress, improved endothelial function and reduced atherosclerotic plaque formation in apoE−/− mice.

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Details

Published: Jul 26, 2013
Vol/Issue: 169(8)
Pages: 1795-1809
License: View

Authors

Z

Zhen Liu

Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre Nanjing Medical University Nanjing China

Y

Yi Han

Department of Geriatrics the First Affiliated Hospital of Nanjing Medical University Nanjing China

L

Ling Li

Department of Chemistry and Pharmacology National University of Singapore Singapore

H

Hui Lu

Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre Nanjing Medical University Nanjing China

G

Guoliang Meng

Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre Nanjing Medical University Nanjing China

X

Xiaozhen Li

Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre Nanjing Medical University Nanjing China

M

Mohammed Shirhan

Department of Chemistry and Pharmacology National University of Singapore Singapore

M

Meng Teng Peh

Department of Chemistry and Pharmacology National University of Singapore Singapore

L

Liping Xie

Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre Nanjing Medical University Nanjing China

S

Suming Zhou

Department of Geriatrics the First Affiliated Hospital of Nanjing Medical University Nanjing China

X

Xiaowei Wang

Department of Cardiothoracic Surgery the First Affiliated Hospital of Nanjing Medical University Nanjing China

Q

Qi Chen

Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre Nanjing Medical University Nanjing China

W

Wei‐Lin Dai

Department of Chemistry and Pharmacology National University of Singapore Singapore

C

Choon‐Hong Tan

Division of Chemistry and Biological Chemistry Nanyang Technological University Singapore

S

Shiyang Pan

Department of Laboratory Medicine The First Affiliated Hospital of Nanjing Medical University Nanjing China

P

P B Moore

Department of Chemistry and Pharmacology National University of Singapore Singapore

Cite This Article

Zhen Liu, Yi Han, Ling Li, et al. (2013). The hydrogen sulfide donor, GYY4137, exhibits anti‐atherosclerotic activity in high fat fed apolipoprotein E−/− mice. British Journal of Pharmacology, 169(8), 1795-1809. https://doi.org/10.1111/bph.12246

The hydrogen sulfide donor, GYY4137, exhibits anti‐atherosclerotic activity in high fat fed apolipoprotein E−/− mice

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