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Cattelan, Arianna (2014) Effetto delle microparticelle endoteliali sulla funzionalitĂ  endoteliale: ruolo di miR-126 e di GLP-1R. [Tesi di dottorato]

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Abstract (inglese)

Introduction: Microparticles are membrane vesicles shed from the plasma membrane of endothelial cells generated in physiological and pathological conditions. Recent studies have shown that EMP may represent important transporters for cytokines, proteins and microRNA. The aim of this study was to investigate, in endothelial cells, the effect of microparticles (EMP) from HCAEC exposed to normal-glucose condition or to high-glucose con-dition (iEMP) on miR-126 expression, on cell proliferation and migration.
Methods: EMP were generated from HCAEC exposed to basal medium without growth supplements for 24 h. Microparticles derived from glucose-trated HCAEC were defined as “injured” EMP (iEMP). HCAEC were in-cubated with EMP or iEMP for 24 h. Microarray analysis was performed by TaqMan microRNA Array. miR-126 expression was determined by qPCR Real-Time, SPRED-1 and GLP-1R protein expression by Western Blot. Cell proliferation was measured using xCELLigence system (Roche) and cell migration by Scratch Assay.
Results: EMP promote cell proliferation and migration by delivering func-tional miR-126 into recipient cells. This leads to downregulation of target protein SPRED-1, a negative modulator of Ras/ERK pathway. iEMP, which contain a lower amount of miR-126 in comparison to EMP, reduce cell pro-liferation by repressing GLP-1R protein expression and by decreasing ERK pathway activation.
Conclusion: This study demonstrates for the first time that endothelial func-tion may be improved by EMP through a release of miR-126 but not in the presence of iEMP. Therefore, EMP may represent a new opportunity to transfer a desired biological message into target cells as therapeutic tool in cardiovascular diseases.

Abstract (italiano)

Introduzione: Le microparticelle (EMP) sono piccole vescicole liberate dalla superficie di membrana di cellule endoteliali in condizioni sia fisiolo-giche che patologiche. Recenti studi hanno messo in evidenza che le EMP rappresentano trasportatori di microRNA capaci di modulare la funzionalità endoteliale con meccanismi non ancora definiti. E’ noto che l’attività proli-ferativa delle cellule endoteliali viene regolata da recettori “accoppiati alla proteina G”, come il recettore GLP-1 (GLP1R).Obiettivo di questo studio è stato di verificare l’effetto delle microparticelle ottenute da cellule cresciute in condizioni di glucosio normale (EMP) o in condizioni di elevato glucosio (iEMP) sull’espressione di miR-126, sulla proliferazione e sulla migrazione cellulare e sulla espressione di GLP1R nelle cellule endoteliali.
Metodi: Le EMP sono state generate incubando cellule endoteliali umane (HCAEC) per 24h in terreno privo di supplementi di crescita. Le iEMP sono state ottenute pre-stimolando le cellule con elevata concentrazione di gluco-sio (30mM) per 72h. In seguito, le cellule HCAEC sono state incubate con le EMP o con le iEMP per 24h. L’analisi di microarray è stata eseguita me-diante TaqMan® microRNA Array. L’espressione genica di miR-126 è stata determinata mediante qPCR Real Time e l’espressione proteica di GLP1R mediante Western Blot. L’effetto proliferativo di EMP, iEMP è stato valuta-to mediante xCELLigence System (Roche) e la migrazione mediante Scratch Assay.
Risultati: Le EMP favoriscono la proliferazione e la migrazione cellulare mediante il trasferimento di miR-126; miR-126 riduce l’espressione di SPRED-1, proteina che regola negativamente la proliferazione cellulare attraverso l'inibizione della via Ras/ERK chinasi; le iEMP invece, hanno un ridotto contenuto di miR-126, attenuano la proliferazione e la migrazione delle cellule endoteliali; è ipotizzabile che tale meccanismo sia dovuto alla riduzione dell’espressione proteica del recettore GLP-1R. La riduzione dell’espressione di GLP-1R indotta da iEMP inibisce l’attivazione di ERK 1/2, direttamente coinvolta nella regolazione della proliferazione cellulare endoteliale.
Conclusione: Questo studio dimostra per la prima volta che i microRNA presenti nelle microparticelle possono agire da mediatori di comunica-zione intercellulare in quanto possono essere trasferiti all’interno di cel-lule target per modularne diverse attività metaboliche, come la prolifera-zione e migrazione cellulare.

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Tipo di EPrint:Tesi di dottorato
Relatore:Fabris, Fabrizio
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > FISIOPATOLOGIA CLINICA E SCIENZE NEFROLOGICHE
Data di deposito della tesi:29 Gennaio 2014
Anno di Pubblicazione:29 Gennaio 2014
Parole chiave (italiano / inglese):Microparticles/Microparticelle microRNA GLP-1
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:6562
Depositato il:05 Nov 2014 14:42
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