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Antezza, Katia (2010) GENETIC VARIANTS C242T and -930 A/G OF THE p22 phox NAD(P)H OXIDASE POLYMORPHISM and VASODILATATION
ENDOTHELIUM-DEPENDENT IN ESSENTIAL HYPERTENSION.
[Tesi di dottorato]

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Abstract (inglese)

Genetic factors and oxidative stress affect endothelial (E) function and has been hypothesized that variants of genes that encode subunit of nicotinamide adenine dinucleotide phosphate oxidase complex (NADPH oxidase), a major source of reactive oxygen species (ROS) are implicated in the pathogenesis of endothelial dysfunction (ED). The latter is a feature of essential hypertension and is considered to play a crucial role in all phases of atherogenesis.
The human p22phox is a subunit of NAD (P) H oxidase, encoded by the gene CYBA, located on the long arm of chromosome 16 in position 24, a large 7.75 kb and consists of six exons and five introns that encode for an open reading frame (ORF) of 600 bp.
There are many SNPs of p22phox, but we have investigated:
• -930 A/G, located in the promoter region at position -930 from the ATG codon. This polymorphism is located on a potential binding site for CCAAT/enhancer-binding the transcription factor C/EBP (CCAAT/enhancer-binding protein);
• C242T on the exon 4.
The aim was to assess whether the two single nucleotide polymorphism (SNPs), -930 A/G and C242 of the p22phox gene (NC_000016.8), corresponds to a different production of superoxide anion (O2°-) involved in the stress oxidative and assess whether these polymorphisms modify the half-life of the enzyme itself.
Examined the role of these two SNPs in fifteen patients, genotyped for both polymorphisms and was conducted a study on endothelial cells extracted from the jugular veins of these patients. Showed that the mutation on the promoter can really change the binding capacity of the transcription factor C/EBP by modulating negatively the transcriptional activity of CYBA and mutation of the exon 4 could reduce oxidative stress.
These results could help the identification of patients at high risk of cardiovascular disease (CAD), beyond the classic risk factors already known.

Abstract (italiano)

Fattori genetici e stress ossidativo alterano la funzione endoteliale (E) ed è stato ipotizzato che varianti dei geni che codificano le subunità della nicotinamina adenina dinucleotide fosfato (NADPH) ossidasi, fonte principale di radicali liberi dell’ossigeno (ROS), siano implicate nella patogenesi della disfunzione endoteliale (DE). Quest’ultima rappresenta un connotato dell’ipertensione arteriosa essenziale ed è ritenuta svolgere un ruolo cruciale in tutte le fasi dell’aterogenesi.
La p22phox umana è una delle subunità della NAD(P)H ossidasi, è codificata dal gene CYBA, collocato sul braccio lungo del cromosoma 16 in posizione 24, grande 7,75 kb e si compone di sei esoni e cinque introni che codificano per un open reading frame (ORF) di circa 600 bp.
Sono noti numerosi SNPs della p22phox, ma quelli da noi esaminati sono stati:
• il -930 A/G che si trova nella regione del promotore, alla posizione -930 dal codone ATG. Questo polimorfismo si trova su un sito potenzialmente vincolante per il fattore di trascrizione C/EBP (CCAAT/enhancer-binding protein);
• il C242T collocato sull’esone4.
Lo scopo del lavoro è stato quello di valutare se ai due single nucleotide polymorphism (SNPs), -930 A/G e C242 del gene p22phox (NC_000016.8), corrisponde una diversa produzione di anione superossido (O2°- ) coinvolto nello stress ossidativo e valutare se i polimorfismi suddetti modificano l’emivita dell’enzima stesso.
E’ stato valutato il ruolo di questi due SNPs in quindici pazienti, genotipizzati per entrambi i polimorfismi ed è stato condotto uno studio sulle cellule endoteliali estratte dalle vene giugulari di questi pazienti.
E’ risultato che la mutazione sul promotore può realmente cambiare la capacità di legame del fattore di trascrizione C/EBP, modulando in maniera negativa l'attività trascrizionale di CYBA e la mutazione sull’esone 4 potrebbe ridurre lo stress ossidativo.
Questi risultati aiuterebbero l’identificazione di pazienti a elevato rischio di malattie cardiovascolari (CAD), al di là dei classici fattori di rischio già conosciuti.

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Tipo di EPrint:Tesi di dottorato
Relatore:Rossi, GianPaolo
Correlatore:Pessina, Achille Cesare
Dottorato (corsi e scuole):Ciclo 21 > Corsi per il 21simo ciclo > IPERTENSIONE ARTERIOSA E BIOLOGIA VASCOLARE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:15 Marzo 2010
Parole chiave (italiano / inglese):NADH/NAD(P)H oxidase Endothelial dysfunction Endothelium-Dependent vasodilatation Nitric Oxide superoxide anion single nucleotide polymorphism
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Clinica e Sperimentale
Codice ID:3067
Depositato il:28 Set 2010 12:44
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