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Métodos Terapéuticos y Terapias MTCI
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1.
Molecules ; 25(20)2020 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-33053898

RESUMEN

Adenosine deaminase (ADA) is an enzyme of purine metabolism that irreversibly converts adenosine to inosine or 2'deoxyadenosine to 2'deoxyinosine. ADA is active both inside the cell and on the cell surface where it was found to interact with membrane proteins, such as CD26 and adenosine receptors, forming ecto-ADA (eADA). In addition to adenosine uptake, the activity of eADA is an essential mechanism that terminates adenosine signaling. This is particularly important in cardiovascular system, where adenosine protects against endothelial dysfunction, vascular inflammation, or thrombosis. Besides enzymatic function, ADA protein mediates cell-to-cell interactions involved in lymphocyte co-stimulation or endothelial activation. Furthermore, alteration in ADA activity was demonstrated in many cardiovascular pathologies such as atherosclerosis, myocardial ischemia-reperfusion injury, hypertension, thrombosis, or diabetes. Modulation of ADA activity could be an important therapeutic target. This work provides a systematic review of ADA activity and anchoring inhibitors as well as summarizes the perspectives of their therapeutic use in cardiovascular pathologies associated with increased activity of ADA.


Asunto(s)
Inhibidores de la Adenosina Desaminasa/uso terapéutico , Animales , Descubrimiento de Drogas/métodos , Proteínas de Choque Térmico/metabolismo , Humanos , Simulación de Dinámica Molecular , Unión Proteica , Agua/química
2.
Nucleosides Nucleotides Nucleic Acids ; 35(10-12): 720-725, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27906619

RESUMEN

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.


Asunto(s)
Nucleótidos de Adenina/metabolismo , Aorta/metabolismo , Aterosclerosis/tratamiento farmacológico , Nucleósidos/farmacología , Piridonas/farmacología , Animales , Aorta/efectos de los fármacos , Aterosclerosis/metabolismo , Evaluación Preclínica de Medicamentos , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Nucleósidos/uso terapéutico , Piridonas/uso terapéutico , Proteína Amiloide A Sérica/metabolismo
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