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Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis.
Circulation. 2019 01 02; 139(1):101-114.Circ

Abstract

BACKGROUND

Hydrogen sulfide (H2S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions.

METHODS

Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E-deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H2S bioavailability, and amino acid profiling were also performed with human material.

RESULTS

The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque H2S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1β. Consistent with the loss of H2S, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R-target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l-cystathionine negatively correlated with vascular reactivity and H2S levels, indicating its potential use as a biomarker for vascular disease.

CONCLUSIONS

The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived H2S prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived H2S are lost owing to the phosphorylation and inhibition of the enzyme.

Authors+Show Affiliations

Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).First Propedeutic Department of Surgery, Vascular Surgery Division, National and Kapodistrian University of Athens Medical School, Greece (F.S., D.I.T., K.A.F., G.Z.).German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Functional Proteomics, SFB 815 Core Unit (J.W., J. Heidler), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).First Propedeutic Department of Surgery, Vascular Surgery Division, National and Kapodistrian University of Athens Medical School, Greece (F.S., D.I.T., K.A.F., G.Z.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. Functional Proteomics, SFB 815 Core Unit (J.W., J. Heidler), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Germany (B.K.).Institute for Cardiovascular Physiology (C. Schürmann, R.P.B.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).First Propedeutic Department of Surgery, Vascular Surgery Division, National and Kapodistrian University of Athens Medical School, Greece (F.S., D.I.T., K.A.F., G.Z.).First Propedeutic Department of Surgery, Vascular Surgery Division, National and Kapodistrian University of Athens Medical School, Greece (F.S., D.I.T., K.A.F., G.Z.).Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.C., D.W.W.).Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.C., D.W.W.).Pharmacentre Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und -Sicherheit (J.P.), Goethe University, Frankfurt am Main, Germany.Institute for Cardiovascular Physiology (C. Schürmann, R.P.B.), Goethe University, Frankfurt am Main, Germany.Laboratory of Pharmacology, Department of Medicine, University of Fribourg, Switzerland (C. Szabo).Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Greece (A.P.). Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece (A.P.).Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany. German Center of Cardiovascular Research, Partner site RheinMain, Frankfurt am Main, Germany (S.-I.B., J. Hu, I.W., J. Heidler, S.Z., V.R., J.W., C. Schürmann, M.S., D.S., B.L., R.A.M., R.P.B., I.F.).

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29970364

Citation

Bibli, Sofia-Iris, et al. "Cystathionine Γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis." Circulation, vol. 139, no. 1, 2019, pp. 101-114.
Bibli SI, Hu J, Sigala F, et al. Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis. Circulation. 2019;139(1):101-114.
Bibli, S. I., Hu, J., Sigala, F., Wittig, I., Heidler, J., Zukunft, S., Tsilimigras, D. I., Randriamboavonjy, V., Wittig, J., Kojonazarov, B., Schürmann, C., Siragusa, M., Siuda, D., Luck, B., Abdel Malik, R., Filis, K. A., Zografos, G., Chen, C., Wang, D. W., ... Fleming, I. (2019). Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis. Circulation, 139(1), 101-114. https://doi.org/10.1161/CIRCULATIONAHA.118.034757
Bibli SI, et al. Cystathionine Γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis. Circulation. 2019 01 2;139(1):101-114. PubMed PMID: 29970364.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis. AU - Bibli,Sofia-Iris, AU - Hu,Jiong, AU - Sigala,Fragiska, AU - Wittig,Ilka, AU - Heidler,Juliana, AU - Zukunft,Sven, AU - Tsilimigras,Diamantis I, AU - Randriamboavonjy,Voahanginirina, AU - Wittig,Janina, AU - Kojonazarov,Baktybek, AU - Schürmann,Christoph, AU - Siragusa,Mauro, AU - Siuda,Daniel, AU - Luck,Bert, AU - Abdel Malik,Randa, AU - Filis,Konstantinos A, AU - Zografos,George, AU - Chen,Chen, AU - Wang,Dao Wen, AU - Pfeilschifter,Josef, AU - Brandes,Ralf P, AU - Szabo,Csaba, AU - Papapetropoulos,Andreas, AU - Fleming,Ingrid, PY - 2018/7/5/pubmed PY - 2019/10/23/medline PY - 2018/7/5/entrez KW - RNA binding proteins KW - atherosclerosis KW - biomarkers KW - cell adhesion molecules KW - hydrogen sulfide SP - 101 EP - 114 JF - Circulation JO - Circulation VL - 139 IS - 1 N2 - BACKGROUND: Hydrogen sulfide (H2S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions. METHODS: Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E-deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H2S bioavailability, and amino acid profiling were also performed with human material. RESULTS: The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque H2S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1β. Consistent with the loss of H2S, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R-target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l-cystathionine negatively correlated with vascular reactivity and H2S levels, indicating its potential use as a biomarker for vascular disease. CONCLUSIONS: The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived H2S prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived H2S are lost owing to the phosphorylation and inhibition of the enzyme. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/29970364/Cystathionine_γ_Lyase_Sulfhydrates_the_RNA_Binding_Protein_Human_Antigen_R_to_Preserve_Endothelial_Cell_Function_and_Delay_Atherogenesis_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.034757?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -