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• W2283670006 abstract "Diabetes mellitus is a major risk factor for cardiovascular diseases. Stimulation of inducible nitric oxide synthase (iNOS) production by inflammatory cytokines causes a significant production of peroxynitrite that is involved in many vascular disorders. In the cardiovascular system, extracellular adenosine has several vasoprotective properties: e.g. it induces vasodilatation, inhibits platelet aggregation, prevents platelet adhesion, inhibits growth of vascular smooth muscle cells (VSMCs) (Ikeda et al., 1997). Several studies demonstrate that in VSMCs adenosine modulates cytokine-induced iNOS expression and thus the release of NO from these cells via A2 receptors (Dubey et al., 1998; St. Hilaire et al., 2008).Since stimulation of iNOS production by inflammatory cytokines is involved in diabetic vascular dysfunction, we investigated the potential role of adenosine in this process by determining its influence on iNOS expression by VSMCs isolated from diabetic as compared to normoglycaemic rats. Diabetes was induced in Sprague-Dawley rats by intravenous injection of streptozotocin (STZ) and VSMCs were isolated from the aorta of control and STZ-diabetic rats 4 weeks after diabetes induction; only animals with blood glucose levels above 300 mg/dl on day 28 were considered diabetic.VSMCs from normal and diabetic rat aortas were incubated for 24 hours in the presence of LPS combined with a cytokine mixture (cytomix) to mimic the in vivo environment of some vascular inflammatory events and were exposed to exogenous adenosine. Incubation of VSMCs with LPS plus cytokine mixture for 24 h induced iNOS expression, which was undetectable in unstimulated VSMCs.Exogenous adenosine (1 mM) did not change iNOS levels in control VSMCs, but potentiated the response to cytokines in diabetic VSMCs. This response was unaffected by the equilibrative nucleoside transporter inhibitor, NBTI, but was further increased (+ 45%) by EHNA, an inhibitor of adenosine deaminase, the enzyme which deaminates adenosine to inosine. Exogenous inosine was ineffective in control and diabetic cells, but the adenosine precursor, AMP, mimicked the effect of adenosine on iNOS production in diabetic cells. Inhibition by AOPCP of ecto-5’-nucleotidase/CD73 (which dephosphorylates AMP in adenosine) did not significantly change iNOS protein levels. In the absence of exogenous adenosine, iNOS expression was reduced after treatment with EHNA in control but not in diabetic VSMCs, demonstrating that adenosine deaminase is responsible for adenosine elimination under non - pathological conditions.An HPLC method was used to quantify AMP, adenosine and their metabolites in the culture medium of VSMCs. At the end of 24 h-incubation, exogenous adenosine was undetectable in the culture medium of control as well as diabetic VSMCs, being converted into inosine and hypoxantine. In control VSMCs NBTI allowed the recovery of half of added adenosine whereas the recovery was lower in diabetic cells, indicating a different contribution of equilibrative transporters to the removal of the nucleoside in diabetes. In contrast, the addition of EHNA did not cause variations in the amount of adenosine recovered in control as compared with diabetic cells. After incubation with AMP, the nucleotide was not detectable and was converted mainly into inosine and hypoxanthine. Treatment with AOPCP allowed 47% recovery of AMP in control, but only 5% recovery in the medium of diabetic VSMCs indicating that diabetes markedly reduced CD73 sensitivity to pharmacological inhibition by AOPCP.These results show that alterations in adenosine-related inflammatory pathways may be present in diabetic vascular dysfunction; in addition, at high concentrations, adenosine seems to lose its protective effect as it stimulates the formation of iNOS, an effect that might be harmful to cells. Thus, diabetes would make VSMCs more sensitive to the potential proinflammatory effect of high concentrations of adenosine in terms of iNOS protein expression." @default.
• W2283670006 created "2016-06-24" @default.
• W2283670006 creator A5091563761 @default.
• W2283670006 date "2011-01-21" @default.
• W2283670006 modified "2023-09-24" @default.
• W2283670006 title "Espressione di iNOS e metabolismo dell'adenosina in cellule muscolari lisce vascolari di ratti diabetici" @default.
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• W2283670006 hasPublicationYear "2011" @default.
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