A Novel Role of Extracellular Nucleotides in Valve Calcification

Osman, Lana; Chester, Adrian H.; Amrani, Mohamed; Frs, Magdi H. Yacoub; Smolenski, Ryszard T.

doi:10.1161/circulationaha.105.001214

Cited by 44 publications

(47 citation statements)

References 19 publications

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“…In contrast, adenosine treatment reduced the activity alkaline phosphatase in human valve interstitial cells cultures in osteogenic media. [7] These findings suggest that changes in the activities that convert ATP to adenosine and then degrade adenosine to inosine could have impact on susceptibility of the valve for pathologies such as calcification and underlies the importance of observations made in present study. A new inherited disorder of nucleotide metabolism causing complete loss of e5NT activity has recently been described.…”

Section: Discussionsupporting

confidence: 70%

Extracellular Adenine Nucleotide Catabolism in Heart Valves

Toczek

Kutryb–Zajac

Kapczyńska

et al. 2014

Nucleosides, Nucleotides and Nucleic Acids

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Enzymes of extracellular nucleotide catabolism, such as ecto-nucleoside triphosphate diphosphohydrolase (eNTPD), ecto-5'-nucleotidase (e5NT) and ecto-adenosine deaminase (eADA), control extracellular concentrations of adenine nucleotides and adenosine, furthermore in that way regulate inflammation, immune response, and platelets aggregation. In valves, disturbances of these processes may lead to their dysfunction and calcification. The aim of this study was to analyze the distribution of enzymes, which are engaged in extracellular nucleotide metabolism on the surface of pig aortic and pulmonary valves in relation to activities in the vessel wall. Activity of e5NT was two times higher on the surface of the aortic valve in comparison to the aorta. The same relation between activity of this enzyme in the pulmonary valve and pulmonary artery can be observed. In contrast, eADA activity on the valve surface is much lower than in the vessel wall. No significant differences were observed between the activity of eNTPD on the valve and the vessel surface. This highlights that pattern of enzymes activities favors the production and retention of adenosine on the valve surface and that its alterations could play a role in valve pathology.

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Section: Discussionsupporting

confidence: 70%

Extracellular Adenine Nucleotide Catabolism in Heart Valves

Toczek

Kutryb–Zajac

Kapczyńska

et al. 2014

Nucleosides, Nucleotides and Nucleic Acids

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“…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: 75%

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

Zukowska

Kutryb–Zajac

Toczek

et al. 2015

Pharmacological Reports

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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.

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“…Other studies have shown that increased inflammatory markers are attributed to shared risk factors with cardiovascular disease and infiltration of lipoproteins and interstitial cells (16,17). Inhibition of the inflammatory activation, possibly by statins (18,19) although not demonstrated in the current study, might be a beneficial pharmacological prevention of AVS. Study limitations.…”

Section: Discussionmentioning

confidence: 62%