Effects of 4-Pyridone-3-carboxamide-1β-D-ribonucleoside on adenine nucleotide catabolism in the aortic wall; Implications for atherosclerosis in ApoE-/-LDLR-/- mice.
4-Pyridone-3-carboxamide-1-beta-D-ribonucleoside (4PYR) is an endogenously produced nucleoside that had been identified as a substrate for intracellular phosphorylation to form intracellular nucleotides. Previous studies demonstrated that 4PYR adversely affects metabolism of endothelial cells that is known risk factor for atherosclerosis. The purpose of this study was to evaluate effects of 4PYR on the progression of atherosclerosis and changes in extracellular nucleotides degradation on the surface of the vessel wall in the murine model.


METHODS
Two month old ApoE-/-LDLR-/- mice were subcutaneously injected with 4PYR (4P) twice per day for one month or with saline in controls (C). Then, at the age of eight month hydrolysis rates of ATP, AMP and adenosine were evaluated in the intact aorta sections by HPLC based assays. Oil Red O (ORO) staining that indicates lipid deposition was quantified spectrophotometrically after extraction from the vessel. Serum amyloid A (SAA) content was analyzed with ELISA.


RESULTS
Adenosine deamination rate (activity of eADA) increased from 8.7±1.4 nmol/min/cm2 in C to 16.0±2.6 nmol/min/cm2 in 4P (p<0.05). AMP dephosphorylation rate (activity of e5NT) and ATP hydrolysis rate (activity of eNTPD) were not different between C and 4P. ORO staining in the aorta of 4P mice increased by 75% as compared to C (p<0.01) while SAA content was similar in both groups.


CONCLUSIONS
This data demonstrated that prolonged exposure to 4PYR of ApoE-/-LDLR-/- mice results in sustained elevation of vascular eADA activity and increased ORO staining indicating endothelial impairment and accelerated atherosclerosis.
['Zabielska|Magdalena|M|', 'Kutryb-Zajac|Barbara|B|', 'Żukowska|Paulina|P|', 'Slominska|Ewa|E|', 'Smoleński|Ryszard|R|']
D000227:Adenine Nucleotides D000818:Animals D001011:Aorta D050197:Atherosclerosis D004353:Drug Evaluation, Preclinical D008297:Male D057507:Mice, 129 Strain D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009705:Nucleosides D011728:Pyridones D000685:Serum Amyloid A Protein
atherosclerosis adenosine 4-Pyridone-3-carboxamide-1β-d-ribonucleoside (4PYR) adenosine deaminase ecto-5′-nucleotidase ecto-nucleoside triphopsphate diphosphohydrolase inflammation