Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis

Sofia Iris Bibli, Jiong Hu, Fragiska Sigala, Ilka Wittig, Juliana Heidler, Sven Zukunft, Diamantis I. Tsilimigras, Voahanginirina Randriamboavonjy, Janina Wittig, Baktybek Kojonazarov, Christoph Schürmann, Mauro Siragusa, Daniel Siuda, Bert Luck, Randa Abdel Malik, Konstantinos A. Filis, George Zografos, Chen Chen, Dao Wen Wang, Josef Pfeilschifter & 4 others Ralf P. Brandes, Csaba Szabo, Andreas Papapetropoulos, Ingrid Fleming

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages101-114
Number of pages14
JournalCirculation
Volume139
Issue number1
DOIs
StatePublished - Jan 2 2019
Externally publishedYes

Fingerprint

Cystathionine gamma-Lyase
RNA-Binding Proteins
Atherosclerosis
Endothelial Cells
cathepsin S
Antigens
Blood Vessels
Carotid Arteries
Ligation
Monocytes
Phosphorylation
Cystathionine
Hydrogen Sulfide
Messenger RNA
Proteins
Dimerization
Apolipoproteins E
Atherosclerotic Plaques
Enzymes
Interleukin-1beta

Keywords

  • atherosclerosis
  • biomarkers
  • cell adhesion molecules
  • hydrogen sulfide
  • RNA binding proteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis. / Bibli, Sofia Iris; Hu, Jiong; Sigala, Fragiska; Wittig, Ilka; Heidler, Juliana; Zukunft, Sven; Tsilimigras, Diamantis I.; Randriamboavonjy, Voahanginirina; Wittig, Janina; Kojonazarov, Baktybek; Schürmann, Christoph; Siragusa, Mauro; Siuda, Daniel; Luck, Bert; Abdel Malik, Randa; Filis, Konstantinos A.; Zografos, George; Chen, Chen; Wang, Dao Wen; Pfeilschifter, Josef; Brandes, Ralf P.; Szabo, Csaba; Papapetropoulos, Andreas; Fleming, Ingrid.

In: Circulation, Vol. 139, No. 1, 02.01.2019, p. 101-114.

Research output: Contribution to journalArticle

Bibli, SI, Hu, J, Sigala, F, Wittig, I, Heidler, J, Zukunft, S, Tsilimigras, DI, Randriamboavonjy, V, Wittig, J, Kojonazarov, B, Schürmann, C, Siragusa, M, Siuda, D, Luck, B, Abdel Malik, R, Filis, KA, Zografos, G, Chen, C, Wang, DW, Pfeilschifter, J, Brandes, RP, Szabo, C, Papapetropoulos, A & Fleming, I 2019, 'Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis', Circulation, vol. 139, no. 1, pp. 101-114. https://doi.org/10.1161/CIRCULATIONAHA.118.034757
Bibli, Sofia Iris ; Hu, Jiong ; Sigala, Fragiska ; Wittig, Ilka ; Heidler, Juliana ; Zukunft, Sven ; Tsilimigras, Diamantis I. ; Randriamboavonjy, Voahanginirina ; Wittig, Janina ; Kojonazarov, Baktybek ; Schürmann, Christoph ; Siragusa, Mauro ; Siuda, Daniel ; Luck, Bert ; Abdel Malik, Randa ; Filis, Konstantinos A. ; Zografos, George ; Chen, Chen ; Wang, Dao Wen ; Pfeilschifter, Josef ; Brandes, Ralf P. ; Szabo, Csaba ; Papapetropoulos, Andreas ; Fleming, Ingrid. / Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis. In: Circulation. 2019 ; Vol. 139, No. 1. pp. 101-114.
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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 - 2019/1/2

Y1 - 2019/1/2

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.

AB - 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.

KW - atherosclerosis

KW - biomarkers

KW - cell adhesion molecules

KW - hydrogen sulfide

KW - RNA binding proteins

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U2 - 10.1161/CIRCULATIONAHA.118.034757

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