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

Abstract

Background and Purpose Atherosclerosis 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 Approach RAW 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 Results GYY4137 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 Implications GYY4137 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.

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

“…Experimental evidence for an antiatherosclerotic effect of H 2 S has been obtained in numerous studies in hyperlipidemic animal and cell models (15,(24)(25)(26), but the antiatherosclerotic effect in the context of diabetes has not been previously investigated. Recent data published by our group demonstrated that treatment with H 2 S decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium-dependent relaxation in ApoE 2/2 mice fed an HFD (15). Exogenous H 2 S improved endotheliumdependent relaxation in isolated vascular rings incubated with HG and attenuated hyperglycemia-induced DNA injury and improved cellular viability in bEnd.3 microvascular endothelial cells (8).…”

“…or vehicle and kept on a high-fat diet (HFD) for 4 weeks. The dose of GYY4137 used was based on previous publications (15). Nondiabetic LDLr 2/2 or LDLr 2/2 Nrf2 2/2 mice were kept on a standard chow diet for 4 weeks as control.…”

Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137

“…In contrast to Na 2 S and NaSH, GYY4137 (morpholin-121 4-ium 4-methoxyphenyl-morpholino-phosphinodithioate) is a donor compound which 122 releases H 2 S at a slow steady rate at physiological pH and temperature (Li et al,123 2008). Several studies have suggested that GYY4137 effectively delivers H 2 S in 124 various physiological systems (Li et al, 2009, Lisjak et al, 2010, Lee et al, 2011 Robinson and Wray, 2012, Liu et al, 2013, Grambow et al, 2014 2015b). Recent work by Meng et al (2015a) showed that GYY4137 given prior to 127 7 …”

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

“…NO and H 2 S share several athero-protective actions, including blood vessel relaxation and regulation of vascular tone, EC regeneration, inhibition of leukocyte adhesion, inhibition of platelet clumping to make the blood thinner, and prevention of proliferation and migration of VSMCs [150][151][152][153]. The role of NO in atherosclerosis development has been studied in apolipoprotein E knockout (apoE-KO) mice, where L-NAME treatment significantly decreased NO-mediated vascular response and increased atherosclerosis development [154].…”

“…H 2 S (50 µM) attenuated H 2 O 2 and oxidized LDL (oxLDL)-mediated endothelial cytotoxicity in HUVECs [161]. GYY4137 (a slow H 2 S releasing molecule) decreased the atherosclerotic plaque formation and partially restored the endothelium-dependent relaxation of apoE-KO mouse aorta [162]. The direct evidence for the role of endogenous H 2 S in atherosclerosis development was reported in 2013, demonstrating that CSE-KO mice fed with atherogenic paigen-type diet, but not WT mice, developed early fatty streak lesions in the aortic root, increased aortic intimal proliferation and aortic adhesion molecule expression, and enhanced oxidative stress [28].…”