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Malorgio, Francesca (2011) Espressione di iNOS e metabolismo dell'adenosina in cellule muscolari lisce vascolari di ratti diabetici. [Tesi di dottorato]

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Abstract (inglese)

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.

Abstract (italiano)

Il diabete è una malattia metabolica associata ad aumentato rischio cardiovascolare. Nel diabete inoltre, in seguito all’attivazione della proteina iNOS, si ha una notevole produzione di perossinitrito che è implicato in molti disordini vascolari.
A livello cardiovascolare l’adenosina manifesta diverse proprietà vasoprotettive: induce infatti vasodilatazione, inibisce l’aggregazione piastrinica e ne previene l’adesione, inibisce la crescita delle cellule muscolari lisce vascolari (VSMC) (Ikeda et al., 1997). Diverse evidenze suggeriscono che l’adenosina prodotta dalle VSMC può indurre i suoi effetti in parte attraverso la produzione di NO a livello della parete dei vasi: il nucleoside, per interazione con i recettori A2, modula l’espressione della proteina iNOS indotta da citochine e di conseguenza il rilascio di NO dalle VSMC (Dubey et al., 1998; St. Hilaire et al., 2008). Dal momento che un’aumentata produzione di iNOS è coinvolta nella disfunzione vascolare diabetica, si è studiato il potenziale ruolo anti-infiammatorio dell’adenosina in tale processo, determinando l’effetto del nucleoside e dei composti ad esso correlati sull’espressione di iNOS in cellule muscolari lisce vascolari di ratti resi diabetici in confronto con ratti normoglicemici. A tale scopo ad una parte degli animali è stato indotto il diabete mediante iniezione nella vena caudale di streptozotocina. Il prelievo dell’aorta dei ratti per l’ottenimento delle colture cellulari è stato effettuato dopo quattro settimane dal trattamento, considerando diabetici solo gli animali con valore di glicemia superiore a 300 mg/dl.
Per indurre l’espressione della proteina iNOS le cellule muscolari lisce vascolari di ratti sani e diabetici sono state stimolate per 24 h con una miscela costituita da LPS più citochine (citomix) e queste cellule sono state trattate con adenosina esogena. Dall’analisi di Western blot emerge che la purina impiegata in concentrazione 1 mM causa un aumento significativo dei livelli di iNOS nelle cellule di ratti diabetici. Questo aumento non è influenzato dal trattamento con NBTI, inibitore dei trasportatori equilibrativi per l’adenosina, ma è potenziato in seguito all’aggiunta di EHNA, inibitore dell’adenosina deaminasi, enzima che converte l’adenosina in inosina. L’inosina esogena non influenza l’espressione di iNOS nelle VSMC controllo e diabetiche, mentre il precursore dell’adenosina, AMP, mima l’effetto dell’adenosina sulla produzione di iNOS nelle cellule diabetiche. L’AOPCP, inibitore dell’enzima CD73, che promuove la defosforilazione di AMP in adenosina, non provoca variazione dell’espressione di iNOS, rispetto al trattamento con solo AMP.
Stimolando le VSMC con citomix e NBTI, EHNA o AOPCP in assenza di purine esogene, si è dimostrato che solo il trattamento con EHNA causa, nelle cellule di ratti normoglicemici, una diminuzione significativa della produzione di iNOS, indicando che l’adenosina deaminasi rappresenta la principale via di eliminazione del nucleoside in condizioni non patologiche.
Le quantità di adenosina rimasta nel medium di incubazione dopo 24 h e quella dei suoi metaboliti sono state monitorate con metodo HPLC. Al termine dell’incubazione l’adenosina scompare dal medium, mentre si accumulano inosina e ipoxantina. Nelle cellule controllo NBTI permette il recupero della metà dell’adenosina inizialmente aggiunta, mentre nelle cellule diabetiche il recupero è inferiore, indicando probabilmente un diverso contributo dei trasportatori equilibrativi alla rimozione del nucleoside nel diabete. Al contrario l’aggiunta di EHNA non causa variazioni nella quantità di adenosina recuperata nelle cellule controllo rispetto a quelle diabetiche.
Anche l’AMP scompare dal medium dopo 24 h con produzione di inosina e ipoxantina; l’aggiunta di AOPCP permette il recupero del 47% del nucleotide nel medium di incubazione delle cellule di ratti sani e solo il 5% nel medium delle cellule di ratti diabetici, suggerendo un’alterazione dell’attività o dell’espressione dell’enzima CD73 associata al diabete.
Questi risultati dimostrano che alterazioni a livello delle vie di eliminazione e formazione dell’adenosina sono presenti nella disfunzione vascolare diabetica. Inoltre, a concentrazioni elevate l’adenosina sembra perdere il suo effetto protettivo, in quanto stimola la formazione di iNOS, con conseguenze che possono essere dannose per la cellula. Il diabete rende, pertanto, le VSMC più sensibili al potenziale effetto proinfiammatorio di elevate concentrazioni di adenosina in termini di espressione della proteina iNOS.

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Tipo di EPrint:Tesi di dottorato
Relatore:Gaion, Rosa Maria
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > SCIENZE FARMACOLOGICHE > FARMACOLOGIA, TOSSICOLOGIA E TERAPIA
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:21 Gennaio 2011
Parole chiave (italiano / inglese):adenosina/adenosin; diabete/diabetes; cellule muscolari lisce vascolari/vascular smooth muscle cells
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Farmacologia ed Anestesiologia "E. Meneghetti"
Codice ID:3334
Depositato il:29 Lug 2011 15:00
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