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Bueno Marinas, Maria (2018) MicroRNA profiling in Arrhythmogenic Cardiomyopathy and prognostic markers. [Ph.D. thesis]

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Abstract (english)

Background: Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease, characterised by a progressive myocardial dystrophy with fibro-fatty replacement, and represents one of the major causes of sudden cardiac death in the young and athletes. Although half of AC patients harbour private desmosomal gene mutations, their low and age-dependent penetrance suggests the involvement of other regulatory molecules. MicroRNAs (miRNAs) are a group of endogenous short noncoding RNAs that regulate gene expression by sequence-specific recognition of their target transcripts. They have been associated with numerous pathophysiological conditions, including cardiovascular diseases; however, their role as key regulatory molecules in AC as well as their impact on the onset and progression of the disease is largely unknown.
Purpose: miRNA profiling in genotype-positive AC-patients with different gene mutations in order to identify their potential as AC biomarkers.
Methods: The study involved 59 subjects with a definite AC diagnosis, previously genotyped, and 14 healthy controls. 84-miRNA array was applied on 8 frozen right-ventricle (RV) myocardial tissue samples, from heart transplanted AC patients; 9 whole blood samples, from patients with definite AC diagnosis, and 6 healthy controls (HC). In the validation study, seven miRNAs were analysed on 42-AC and 8-HC blood samples. miRNA analysis was performed by qPCR, relative quantification ΔΔCt method and in silico target prediction. All data were expressed in fold-change values. Receiver operating characteristic (ROC) analysis was performed on validated miRNAs.
Results: miRNA profiling on AC-tissue samples displayed a genotype-related profile, 19 miRNAs were differentially expressed in PKP2 carriers, 15 in DSP carriers and 14 in DSG2 carriers, when compared to healthy controls. A common signature between PKP2 and DSP carriers was identified with 14 miRNAs in common (PKP2/DSP profile). None of these miRNAs were shown within DSG2 profile. In silico target prediction identified Hippo Signaling Pathway as a common target for both profiles. Analysis of AC-tissue samples as a unique group confirmed 26 differentially expressed miRNAs (AC-tissue profile) with predicted targets in the AC pathway. AC-blood miRNA profiling demonstrated a 14-miRNA signature, with 10 miRNAs differentially expressed in common with AC-tissue profile. Hsa-miR-144-3p, -122-5p, -208a-3p and -494-3p as well as hsa-miR-21-5p, -155-5p and -320a were analysed on a larger cohort of 42-AC and 8-HC. Only hsa-mir-122-5p was significantly overexpressed (p-value<0,05). ROC analysis showed hsa-miR-122-5p to be a potential AC biomarker (area under the curve: 0.83).
Conclusions: A genotype-related miRNA profile was observed in AC-tissue samples, as to reflect clinical variability. In addition, 10 miRNAs in common were identified between AC-tissue and AC-blood profiles, proving a specific miRNA signature for AC. These miRNA profiles targeted pathways involved in AC pathogenesis demonstrating their key roles in the onset and progression of the disease. Circulating level of hsa-miR-122-5p was significantly elevated in AC subjects, demonstrating its potential as a prognostic marker for heart failure in AC.

Abstract (italian)

Introduzione. La Cardiomiopatia Aritmogena (AC) è una malattia clinicamente e geneticamente eterogenea del miocardio, caratterizzata da una progressiva distrofia miocardica con sostituzione fibro-adiposa, e rappresenta una delle principali cause di morte improvvisa nei giovani e negli atleti. Nonostante circa la metà dei pazienti affetti da AC presentino mutazioni nei geni desmosomiali, la bassa penetranza e dipendenza dall’età della patologia suggeriscono il coinvolgimento di altre molecole regolatrici. I microRNA (miRNA) sono un gruppo di molecole endogene, di RNA non codificante, che regolano l'espressione genica mediante lo specifico riconoscimento di sequenze target dei trascritti. Sono stati associati a numerose condizioni patofisiologiche, tra cui malattie cardiovascolari; tuttavia, il loro ruolo come molecole regolatrici nella AC e il loro impatto sull'insorgenza e sulla progressione della malattia è in gran parte sconosciuto.
Scopo dello studio. Analizzare il profilo di espressione dei miRNA in pazienti affetti da AC genotipicamente positivi allo scopo di studiare il loro potenziale come biomarcatori prognostici. Materiali e metodi. Lo studio ha coinvolto 59 soggetti con una diagnosi clinica di AC, precedentemente genotipizzati, e 14 controlli sani (HC). Un array composto da 84-miRNA è stato testato su: 8 campioni di tessuto miocardico congelato del ventricolo destro, proveniente da pazienti trapiantati affetti da AC; 9 campioni di sangue intero congelato, da pazienti con diagnosi clinica di AC e 6 controlli sani. Nella fase di validazione sono stati analizzati sette miRNA su campioni di sangue provenienti da 42-AC e 8-HC. L'analisi è stata eseguita mediante qPCR seguita da quantificazione relativa con il metodo ΔΔCt e predizione in silico dei geni target. I risultati sono stati espressi in valori di “fold-change” e le curve ROC (Receiver Operating Characteristic) analizzate sui miRNA validati.
Risultati. L’analisi dei miRNA su 8 campioni di tessuto di pazienti affetti da AC mostrava un profilo correlato al genotipo rispetto ai controlli sani, in particolare: 19 miRNA erano differenzialmente espressi nei portatori di una mutazione in PKP2, 15 nei portatori di una mutazioni in DSP e 14 nei portatori di una mutazione in DSG2. E’ stato identificato un profilo d’espressione in comune tra i portatori della mutazione in PKP2 e i portatori della mutazione in DSP, con 14 miRNA alterati (profilo PKP2/DSP). Nessuno di questi miRNA è stato trovato nel profilo DSG2. Lo studio in silico dei possibili geni target ha identificato la via di segnale “Hippo Signaling Pathway” come target comune per entrambi i profili (PKP2/DSP- DSG2). Considerando i campioni di tessuto AC come un unico gruppo indipendentemente dal gene mutato sono emersi 26 miRNA differenzialmente espressi (profilo AC-tessuto) che hanno come target geni coinvolti nel pathway AC. Lo studio dei miRNA nei 9 campioni di sangue dei pazienti affetti da AC ha dimostrato un profilo costituito 14-miRNA alterati, dei quali 10 alterati anche nel profilo AC-tessuto. Hsa-miR-144-3p, -122-5p, -208a-3p e -494-3p così come hsa-miR-21-5p, -155-5p e -320a sono stati infine validati su una coorte più ampia di 42-AC e 8-HC. Solo hsa-mir-122-5p è stato riscontrato come significativamente sovraespresso (valore p <0,05). L'analisi di curve ROC ha mostrato che hsa-miR-122-5p è un potenziale biomarcatore di AC (AUC: 0.83).
Conclusione. Nei campioni AC di tessuto è stato osservato un profilo di miRNA correlato al genotipo, tale da rispecchiare la variabilità clinica della patologia. Inoltre, sono stati identificati 10 miRNA in comune tra i profili dei campioni AC di tessuto e sangue, evidenziando un profilo di espressione di miRNA specifico per AC. Entrambi i profili infatti (tessuto e sangue) hanno come target vie di segnale coinvolte nella patogenesi della AC, dimostrando un ruolo chiave nella insorgenza e la progressione della malattia. In particolare il livello di hsa-miR-122-5p in circolo era significativamente elevato nei soggetti affetti da AC, dimostrando il suo potenziale come marcatore prognostico della malattia.

EPrint type:Ph.D. thesis
Tutor:Basso, Cristina
Supervisor:Pilichou, Kalliopi
Ph.D. course:Ciclo 30 > Corsi 30 > MEDICINA SPECIALISTICA "G.B. MORGAGNI"
Data di deposito della tesi:12 January 2018
Anno di Pubblicazione:12 January 2018
Key Words:MicroRNA, miRNA, Arrhythmogenic Cardiomyopathy, AC, biomarker
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Istituti > Istituto di Anatomia Patologica
Codice ID:10716
Depositato il:09 Nov 2018 10:41
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