apyrase and Heart-Defects--Congenital

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

Topics: 5'-Nucleotidase; Adenosine Triphosphate; Animals; Antigens, CD; Aortic Valve; Aortic Valve Stenosis; Apyrase; Bicuspid Aortic Valve Disease; Calcinosis; Cell Culture Techniques; Cellular Microenvironment; Heart Defects, Congenital; Heart Valve Diseases; Phosphoric Diester Hydrolases; Purinergic Agents; Pyrophosphatases; Receptor, Adenosine A2A; Receptor, Adenosine A2B; Sheep; Signal Transduction; Up-Regulation