Kun Zhou , Wen Luo , Dan-Dan Gui , Zhong Ren , Dang-Heng Wei , Lu-Shan Liu , Guo-Hua Li , Zhi-Han Tang , Wen-Hao Xiong , Heng-Jing Hu , Zhi-Sheng Jiang
{"title":"硫化氢通过巯基化内皮细胞NFIL3抑制MEST介导的内皮间质转化，减轻低剪切应力诱导的动脉粥样硬化。","authors":"Kun Zhou , Wen Luo , Dan-Dan Gui , Zhong Ren , Dang-Heng Wei , Lu-Shan Liu , Guo-Hua Li , Zhi-Han Tang , Wen-Hao Xiong , Heng-Jing Hu , Zhi-Sheng Jiang","doi":"10.1016/j.niox.2023.11.005","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p><span>Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H</span><sub>2</sub>S), a protective gaseous mediator in atherosclerosis and the process of EndMT.</p></div><div><h3>Methods</h3><p>We constructed a stable low-shear-stress-induced(2 dyn/cm<sup>2</sup>) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE<sup>−/−</sup> mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE<sup>−/−</sup> mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV).</p></div><div><h3>Results</h3><p><span>These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H</span><sub>2</sub><span><span>S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and </span>Luciferase<span> Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H</span></span><sub>2</sub>S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H<sub>2</sub><span>S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration.</span></p></div><div><h3>Conclusions</h3><p>H<sub>2</sub>S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.</p></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2000,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation\",\"authors\":\"Kun Zhou , Wen Luo , Dan-Dan Gui , Zhong Ren , Dang-Heng Wei , Lu-Shan Liu , Guo-Hua Li , Zhi-Han Tang , Wen-Hao Xiong , Heng-Jing Hu , Zhi-Sheng Jiang\",\"doi\":\"10.1016/j.niox.2023.11.005\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p><span>Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H</span><sub>2</sub>S), a protective gaseous mediator in atherosclerosis and the process of EndMT.</p></div><div><h3>Methods</h3><p>We constructed a stable low-shear-stress-induced(2 dyn/cm<sup>2</sup>) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE<sup>−/−</sup> mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE<sup>−/−</sup> mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV).</p></div><div><h3>Results</h3><p><span>These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H</span><sub>2</sub><span><span>S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and </span>Luciferase<span> Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H</span></span><sub>2</sub>S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H<sub>2</sub><span>S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration.</span></p></div><div><h3>Conclusions</h3><p>H<sub>2</sub>S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.</p></div>\",\"PeriodicalId\":19357,\"journal\":{\"name\":\"Nitric oxide : biology and chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2023-12-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nitric oxide : biology and chemistry\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1089860323001039\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nitric oxide : biology and chemistry","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1089860323001039","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation
Background
Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT.
Methods
We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE−/− mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE−/− mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV).
Results
These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration.
Conclusions
H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.
期刊介绍：
Nitric Oxide includes original research, methodology papers and reviews relating to nitric oxide and other gasotransmitters such as hydrogen sulfide and carbon monoxide. Special emphasis is placed on the biological chemistry, physiology, pharmacology, enzymology and pathological significance of these molecules in human health and disease. The journal also accepts manuscripts relating to plant and microbial studies involving these molecules.
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