Extracellular Adenine Nucleotide Catabolism in Heart Valves

Toczek, Marta; Kutryb–Zajac, Barbara; Kapczyńska, Małgorzata; Lipiński, Marcin; Słomińska, Ewa; Smoleński, Ryszard T.

doi:10.1080/15257770.2014.880479

Cited by 6 publications

(6 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First we found CD73 activity among the highest in the human body [10,46]. Furthermore, we found that human valve interstitial cells could be shifted toward osteoblast phenotype with high alkaline phosphatase activity by exposure to ATP or non-hydrolizable ATP analog while exposure to adenosine block this transformation [47].…”

Section: Cd73 and Arterial Calcificationsmentioning

confidence: 93%

See 1 more Smart Citation

The role of ecto-5′-nucleotidase in endothelial dysfunction and vascular pathologies

Zukowska

Kutryb–Zajac

Toczek

et al. 2015

Pharmacological Reports

Self Cite

View full text Add to dashboard Cite

Ecto-5'-nucleotidase (e5NT, CD73) is an enzyme that is highly expressed in endothelium and is involved in the extracellular nucleotide catabolism. CD73 converts AMP to adenosine that via specific subtypes of P1 receptor mediates cytoprotection involving diverse mechanisms such as vasodilatation, suppression of inflammation, inhibition of thrombosis and anti-adrenergic effect. Physiological intravascular concentration of adenosine is in nanomolar range, but could become micromolar in response to various forms of stress. Endothelium is a major site for both CD73 mediated production of adenosine and its cytoprotective effect. Nucleotides (predominantly ATP or ADP) that could be released from different cells via controlled specific of unspecific mechanisms constitute a major source of substrate for adenosine production via CD73. Direct effects of extracellular nucleotides (mediated by P2 receptors) are typically opposite to adenosine P1 mediated activities. Retention of nucleotides and decreased adenosine production due to loss of CD73 function may have negative implications and could be important cause of various pathologies. Protective role of CD73 was indicated in ectopic calcification, atherosclerosis, rejection after xenotransplantation and thrombosis. Reduced activity of CD73 due to lymphocyte contact with endothelium increases its permeability that leads to enhanced leukocyte transmigration. Upregulation of endothelial CD73 may therefore be protective in a number of cardiovascular pathologies. Such effect has been confirmed for some common drugs such as statins and it could be part of its pleiotropic portfolio. Activation of CD73 could be a new target for specific treatment strategy that in particular will enhance endothelial protection.

show abstract

Section: Cd73 and Arterial Calcificationsmentioning

confidence: 93%

“…The presence of this enzyme is also confirmed on leukocytes derived from peripheral blood, thymus, spleen and lymph node. Such widespread organ distribution is related to its high abundance in endothelium [9,10]. Ecto-5 0 -nucleotidase is also expressed by a considerable variety of tumor cells [11].…”

Section: Cd73: Cellular Function and Structurementioning

confidence: 99%

The role of ecto-5′-nucleotidase in endothelial dysfunction and vascular pathologies

Zukowska

Kutryb–Zajac

Toczek

et al. 2015

Pharmacological Reports

Self Cite

View full text Add to dashboard Cite

show abstract

“…7A). There was a significant (p<0.05) down-regulation of transcripts involved in adenine nucleotide synthesis and conversion, such as Entpd2 (Ectonucleoside triphosphate diphosphohydrolase 2) and Nme3 (Nucleoside diphosphate kinase 3) [30,31], but only in the HdhQ150 mouse model (p<0.05) (Fig. 7B).…”

Section: Transcriptional Remodeling Of Genes Involved In the Synthesimentioning

confidence: 99%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Self Cite

View full text Add to dashboard Cite

Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

show abstract

“…Nucleotides may also be catabolized by other enzymes such as ecto-nucleotide pyrophosphatases/ phosphodiesterases (eNPPs) or alkaline phosphatase (ALP) [22,23]. Upstream pathways, which lead to extracellular ATP synthesis from AMP are the least important, because of the minimal ecto-kinase activity [24]. Except for the removal of nucleotides from the extracellular space, the significant function of ecto-nucleotidases is the production of adenosine, which attenuates inflammation and platelets reactivity [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

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

show abstract

Extracellular Adenine Nucleotide Catabolism in Heart Valves

Cited by 6 publications

References 11 publications

The role of ecto-5′-nucleotidase in endothelial dysfunction and vascular pathologies

The role of ecto-5′-nucleotidase in endothelial dysfunction and vascular pathologies

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

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

Contact Info

Product

Resources

About