Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC

Jin, Hui; Hilaire, Cynthia St.; Huang, Yuting; Yang, Dan; Dmitrieva, Natalia I.; Negro, Alejandra; Schwartzbeck, Robin; Liu, Yangtengyu; Yu, Zhen; Walts, Avram D.; Davaine, Jean-Michel; Lee, Duck‐Yeon; Donahue, Danielle; Hsu, Kevin; Chen, Jessica; Tien, Cheng; Gahl, William A.; Chen, Guibin; Boehm, Manfred

doi:10.1126/scisignal.aaf9109

Cited by 66 publications

(49 citation statements)

References 52 publications

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“…Patients with mutations in CD73 gene exhibited ectopic calcification within the cardiovascular system that was dependent on the lack of TNAP-inhibiting adenosine. [65] These reports suggest that inhibitors of TNAP, such as adenosine, could be considered as potential preventive strategies in CAVD and supporting this hypothesis, we observed decreased serum and aortic root ALP activity in ApoE−/−LDLR−/− mice treated with adenosine deaminase inhibitor.…”

Section: Discussionsupporting

confidence: 87%

“…[66] On the contrary, treatment with A2bR agonist significantly reduced the calcification volume of progenitor cell-derived teratomas from patients with CD73 deficiency. [65] Also in our recent work, we have shown that CD73−/− mice spontaneously developed aortic valve dysfunction increasing peak aortic flow and valvular Fig. 6 Adenosine receptors are widely express in human non-stenotic and stenotic aortic valves.…”

Section: Discussionmentioning

confidence: 92%

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Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

et al. 2019

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Background Extracellular nucleotide metabolism contributes to chronic inflammation, cell differentiation, and tissue mineralization by controlling nucleotide and adenosine concentrations and hence its purinergic effects. This study investigated location-specific changes of extracellular nucleotide metabolism in aortic valves of patients with calcific aortic valve disease (CAVD). Individual ecto-enzymes and adenosine receptors involved were analyzed together with correlation with CAVD severity and risk factors. Results Nucleotide and adenosine degradation rates were adversely modified on the aortic surface of stenotic valve as compared to ventricular side, including decreased ATP removal (1.25 ± 0.35 vs. 2.24 ± 0.61 nmol/min/cm 2 ) and adenosine production (1.32 ± 0.12 vs. 2.49 ± 0.28 nmol/min/cm 2 ) as well as increased adenosine deamination (1.28 ± 0.31 vs. 0.67 ± 0.11 nmol/min/cm 2 ). The rates of nucleotide to adenosine conversions were lower, while adenosine deamination was higher on the aortic sides of stenotic vs. non-stenotic valve. There were no differences in extracellular nucleotide metabolism between aortic and ventricular sides of non-stenotic valves. Furthermore, nucleotide degradation rates, measured on aortic side in CAVD (n = 62), negatively correlated with echocardiographic and biochemical parameters of disease severity (aortic jet velocity vs. ATP hydrolysis: r = − 0.30, p < 0.05; vs. AMP hydrolysis: r = − 0.44, p < 0.001; valvular phosphate concentration vs. ATP hydrolysis: r = − 0.26, p < 0.05; vs. AMP hydrolysis: r = − 0.25, p = 0.05) while adenosine deamination showed positive correlation trend with valvular phosphate deposits (r = 0.23, p = 0.07). Nucleotide and adenosine conversion rates also correlated with CAVD risk factors, including hyperlipidemia (AMP hydrolysis vs. serum LDL cholesterol: r = − 0.28, p = 0.05; adenosine deamination vs. total cholesterol: r = 0.25, p = 0.05; LDL cholesterol: r = 0.28, p < 0.05; triglycerides: r = 0.32, p < 0.05), hypertension (adenosine deamination vs. systolic blood pressure: r = 0.28, p < 0.05) and thrombosis (ATP

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 92%

Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

et al. 2019

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“…However, treatment with adenosine with or without the latter inhibitors enhanced the biomineralization of VICs, indicating that CD73 plays a central role in regulating pericellular adenosine levels, thus acting as a gatekeeper. Adenosine is known to down-regulate the neutral ALP (tissuenonspecific ALP, TNAP), and thereby reduces the calcification process by inhibiting the degradation of PP i to P i in vasculature and myocardium (43). For the latter tissue types, a consequent reduction of extracellular adenosine levels enhances TNAP activity, which promotes the calcification process (17,43,44).…”

Section: Discussionmentioning

confidence: 99%

“…Adenosine is known to down-regulate the neutral ALP (tissuenonspecific ALP, TNAP), and thereby reduces the calcification process by inhibiting the degradation of PP i to P i in vasculature and myocardium (43). For the latter tissue types, a consequent reduction of extracellular adenosine levels enhances TNAP activity, which promotes the calcification process (17,43,44). In our model, the degeneration of VICs is induced by an experimental increase in the availability of P i , so that the inhibiting effect of TNAP can be neglected.…”

Section: Discussionmentioning

confidence: 99%

Enzymes of the purinergic signaling system exhibit diverse effects on the degeneration of valvular interstitial cells in a 3‐D microenvironment

et al. 2018

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Calcific aortic valve disease is an active disease process with lipoprotein deposition, chronic inflammation, and progressive leaflet degeneration. Expression of ectonucleotidases, a group of membrane-bound enzymes that regulate the metabolism of ATP and its metabolites, may coregulate the degeneration process of valvular interstitial cells (VICs). The aim of this study was to investigate the role of the enzymes of the purinergic system in the degeneration process of VICs. Ovine VICs were cultivated in vitro under different prodegenerative conditions and treated with inhibitors of ectonucleoside triphosphate diphosphohydrolase 1 (CD39)/ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and 5'-nucleotidase (CD73), as well as with adenosine and adenosine receptor agonists. Experiments were performed both in 2-dimensional (2-D) and 3-dimensional (3-D) cell-culture models. Our main findings were that VICs continuously release ATP. Inhibition of ATP hydrolyzing enzymes (CD39 and ENPP1) resulted in profound prodegenerative effects with a vigorous up-regulation of CD39, ENPP1, and CD73, as well as TGF-β1 and osteopontin at the gene level. In our 3-D model, the effect was more pronounced than in 2-D monolayers. Increasing adenosine levels, as well as stimulating the adenosine receptors A and A, exhibited strong prodegenerative effects, whereas conversely, lowering adenosine levels by inhibition of CD73 resulted in protective effects against degeneration. Dysregulation of any one of these enzymes plays an important role in the degeneration process of VICs. Stimulation of ATP and adenosine has prodegenerative effects, whereas lowering the adenosine levels exerts a protective effect.-Weber, A., Barth, M., Selig, J. I., Raschke, S., Dakaras, K., Hof, A., Hesse, J., Schrader, J., Lichtenberg, A., Akhyari, P. Enzymes of the purinergic signaling system exhibit diverse effects on the degeneration of valvular interstitial cells in a 3-D microenvironment.

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“…(54) We also demonstrated that immunofluorescence signal for 16 both proteins, alkaline phosphatase and eNPP1 was abundant in stenotic aortic valves, 17 with significant accumulation of alkaline phosphatase within the calcification areas.18 Patients with mutations in e5NT gene exhibited ectopic calcification within the 19 cardiovascular system. (55) These reports suggest that inhibitors of TNAP, like 20 adenosine, could be considered as potential preventive strategies in CAVD (56). 21 However, these beneficial adenosine effects could be also dependent on the type of 22 activated adenosine receptors and the activity of endothelial or immune cell-surface 23 ecto-adenosine deaminase.…”

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confidence: 99%

Extracellular Adenine Nucleotide and Adenosine Metabolism in Calcific Aortic Valve Disease

Kutryb–Zajac

Jabłońska

Serocki

et al. 2018

Preprint

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3031 Keywords: calcific aortic valve disease, ecto-5'-nucleotidase, ecto-nucleoside 32 triphosphate diphosphohydrolase 1, adenosine deaminase, adenosine, adenosine 33 receptors 2 1 Abstract 2 Extracellular nucleotide catabolism contributes to immunomodulation, cell 3 differentiation and tissue mineralization by controlling nucleotide and adenosine 4 concentrations and its purinergic effects. Disturbances of purinergic signaling in valves 5 may lead to its calcification. This study aimed to investigate the side-specific changes 6 in extracellular nucleotide and adenosine metabolism in the aortic valve during calcific 7 aortic valve disease (CAVD) and to identify the individual enzymes that are involved 8 in these pathways as well as their cellular origin. 9 Stenotic aortic valves were characterized by reduced levels of extracellular ATP 10 removal and impaired production of adenosine. Respectively, already reduced levels of 11 extracellular adenosine were immediately degraded further due to the elevated rate of 12 adenosine deamination. For the first time, we revealed that this metabolic pattern was 13 observed only on the fibrosa surface of stenotic valve that is consistent with the mineral 14 deposition on the aortic side of the valve. Furthermore, we demonstrated that non-15 stenotic valves expressed mostly ecto-nucleoside triphosphate diphosphohydrolase 1 16 (eNTPD1) and ecto-5'nucleotidase (e5NT), while stenotic valves ecto-nucleotide 17 pyrophosphatase/ phosphodiesterase 1, alkaline phosphatase and ecto-adenosine 18 deaminase (eADA). On the surface of endothelial cells, isolated from non-stenotic 19 valves, high activities of eNTPD1 and e5NT were found. Whereas, in valvular 20 interstitial cells, eNPP1 activity was also detected. Stenotic valve immune infiltrate was 21 an additional source of eADA. We demonstrated the presence of A1, A2a and A2b 22 adenosine receptors in both, non-stenotic and stenotic valves with diminished 23 expression of A2a and A2b in the former.24 Extracellular nucleotide and adenosine metabolism that involves complex ecto-enzyme 25 pathways and adenosine receptor signaling were adversely modified in CAVD. In 26 particular, diminished activities of eNTPD1 and e5NT with the increase in eADA that 27 originated from valvular endothelial and interstitial cells as well as from immune 28 inflitrate may affect aortic valve extracellular nucleotide concentrations to favor a pro-29 inflammatory milieu, highlighting a potential mechanism and target for CAVD therapy. 30 31

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Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC

Cited by 66 publications

References 52 publications

Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

Enzymes of the purinergic signaling system exhibit diverse effects on the degeneration of valvular interstitial cells in a 3‐D microenvironment

Extracellular Adenine Nucleotide and Adenosine Metabolism in Calcific Aortic Valve Disease

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