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Deshwal, Soni (2017) Mitochondrial ROS formation catalyzed by monoamine oxidase is causally related to inflammation, fibrosis and diastolic dysfunction in type 1 diabetic hearts. [Tesi di dottorato]

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Abstract (inglese)

Cardiovascular disease is the leading cause of death among diabetic patients. Amongst various mechanisms proposed to contribute to the development of diabetic cardiomyopathy, oxidative stress has received significant experimental and clinical evaluation. However, large scale clinical trials using antioxidant therapies for the treatment of these pathological disorders have been ineffective. Collectively, these studies point towards a serious need to develop therapeutic strategies aimed at inhibiting specific sources of reactive oxygen species (ROS). In the present thesis, we investigated the role of monoamine oxidases (MAOs), outer mitochondrial enzymes that generate HβOβ, in oxidative stress and mitochondrial dysfunction in cardiomyocytes exposed to diabetic milieu and cardiac damage in type 1 diabetes (T1D) mice in vivo.
Initially, we assessed ROS formation and mitochondrial function in primary cardiomyocytes treated with high glucose (HG) and/or interleukin-1β (IL-1β), a proinflammatory cytokine found to be elevated in diabetic patients. Cells exposed to these stimuli displayed an increase in ROS formation which was accompanied by mitochondrial dysfunction as documented by decreased mitochondrial membrane potential. MAO inhibitor pargyline completely prevented these alterations, suggesting that HG and IL-1β induce ROS
formation and mitochondrial dysfunction in a MAO-dependent manner. Moreover, to study whether MAO activity is also involved in endoplasmic reticulum (ER)-mitochondria crosstalk and activation of unfolded protein response (UPR), we assessed markers of ER stress in this model. Interestingly, in adult cardiomyocytes, protein expression of activating transcription factor 4 (ATF4), growth arrest and DNA damage-inducible protein (GADDγ4), 78 kDa glucose-regulated protein (GRP78) and phosphorylation levels of IRE1α (inositolrequiring enzyme 1α) were significantly upregulated, marking the clear occurrence of ER stress. Pargyline administration abrogated these changes, suggesting that MAO is involved in HG and IL-1β induced UPR. Moreover, this suggests that, at least in this setting, MAOdependent ROS formation is upstream of ER stress, and play an important role in the crosstalk between mitochondria, inflammation and ER stress occurring in cardiomyocytes exposed to diabetic milieu.
Given the involvement of MAO in HG and IL-1β induced cell damage, we investigated its role in cardiac dysfunction in streptozotocin (STZ)-induced T1D. We found that diastolic stiffness, an index of diastolic dysfunction, was significantly increased in STZ mice, whereas ejection fraction, an index of systolic function, remained unchanged. Moreover, markers of oxidative stress (4-hydroxynonenal) and UPR (ATF4 and GADDγ4) were significantly increased in STZ hearts as compared to controls. Importantly, STZ mice treated with MAO inhibitor pargyline displayed preserved diastolic function and absence of ER and oxidative stress. In agreement with previous reports showing that fibrosis is one of the major features of diabetic cardiomyopathy, we found that hearts from STZ-treated mice displayed increased collagen deposition. Interestingly, pargyline administration prevented this alteration, suggesting that MAO activity plays a crucial role in the progression of fibrosis in these animals. To understand whether MAO-mediated fibrosis was due to release of proinflammatory and pro-fibrotic factors from cardiac mast cells, we assessed mast cell degranulation. Indeed, mast cell degranulation increased by almost β-fold in STZ hearts as compared to control mice. MAO inhibition completely blocked the activation of mast cells in diabetic mice. These data indicate the novel role of these flavoenzymes in activating cardiac mast cell thereby leading to the remodeling of the extracellular matrix, fibrosis and ultimately, left ventricle (LV) dysfunction in T1D.
Collectively, these results demonstrate that MAOs not only contribute to HG and inflammation induced mitochondrial ROS formation and dysfunction, but they also perturb ER function leading to the activation of UPR. Moreover, we showed that these flavoenzymes
play a major role in the formation of a vicious cycle between oxidative stress and inflammation, which is likely the underlying cause of cardiac fibrosis and LV diastolic dysfunction in T1D mice. MAO inhibitors are clinically available and are being used for the treatment of several neurological and neurodegenerative diseases. Results from our study suggest that MAO inhibition could be a promising therapeutic strategy also for the treatment of cardiovascular complications in diabetes.

Abstract (italiano)

Le malattie cardiovascolari sono le principali cause di morte tra i pazienti diabetici. Tra i vari meccanismi che contribuiscono allo sviluppo della cardiomiopatia diabetica, lo stress ossidativo ha ricevuto un’attenzione clinica e sperimentale significativa. Tuttavia, l’uso di terapie antiossidanti in studi clinici su larga scala è risultato inefficace nel trattamento di questi disturbi patologici. Nel complesso, questi studi indicano una reale necessità di sviluppare strategie terapeutiche volte a inibire specifiche fonti di specie reattive dell'ossigeno (ROS). Lo scopo di questa tesi è stato quello di valutare il ruolo delle monoammino ossidasi (MAO), enzimi mitocondriali localizzati nella membrana esterna, nello stress ossidativo e nella disfunzione mitocondriale in cardiomiociti esposti ad elevate concentrazione di glucosio (in vitro) ed il loro contributo in vivo nei danni cardiaci in un modello di T1D.
Inizialmente, abbiamo valutato la formazione di ROS e la funzione mitocondriale in cardiomiociti primari trattati con alti livelli di glucosio (HG) e/o interleuchina-1β (IL-1β), una citochina pro-infiammatoria presente in livelli elevati in pazienti diabetici. Le cellule esposte a questi stimoli mostrano un aumento della formazione di ROS, accompagnata da disfunzione mitocondriale, come determinato dal minore potenziale di membrana mitocondriale. La pargilina, un inibitore MAO, previene completamente queste alterazioni, suggerendo che HG e IL-1β inducano la formazione di ROS e le disfunzione mitocondriale MAO-dipendente.
Inoltre, per valutare se l’attività della MAO sia coinvolta nell’interazione tra i mitocondri ed il reticolo endoplasmatico (ER) e se possa determinare l’attivazione del’Unfolded Protein Response (UPR), in questo modello abbiamo misurato marcatori di stress dell’ER. È interessante notare come, in cardiomiociti adulti, l'espressione della proteina transcription factor 4 (ATF4), della growth arrest and DNA damage-inducible protein (GADD34), 78 kDa glucose-regulated protein (GRP78) e i livelli di fosforillazione di IRE1α (inositol-requiring enzyme 1α) siano significativamente elevati, il che dimostra la chiara presenza di stress del reticolo (ER). La somministrazione di pargilina previene e blocca queste alterazioni, suggerendo che MAO sia coinvolto nel processo di UPR indotto dalla combinazione di alto glucosio e IL-1β. Inoltre questi dati suggeriscono che, almeno in queste condizioni, la formazione di ROS MAO-dipendente è a monte dello stress del reticolo (ER) e svolge un ruolo importante nell’interazione tra mitocondri, infiammazione del reticolo in cardiomiociti esposti a condizioni simulanti il diabete.
Dato il coinvolgimento della MAO nel danno cellulare causato da HG e IL-1β, abbiamo valutato il suo ruolo nella disfunzione cardiaca in modelli murini di diabete di tipo 1 (T1D) indotta da trattamento con streptozotocina (STZ). La rigidità diastolica, un indice di disfunzione diastolica, era significativamente aumentata nei topi STZ, mentre la frazione di eiezione, un indice di funzione sistolica, è rimasta invariata. Inoltre, i marcatori di stress ossidativo (4-idrossinonenale) e UPR (ATF4 e GADD34) sono risultati significativamente aumentati nei cuori STZ rispetto al controllo. È importante sottolineare come i topi diabetici trattati con la pargilina, inibitore specifico per MAO, abbiano mostrato una funzione diastolica preservata e l’assenza di stress ossidativo e dell’ ER. In accordo con studi precedenti dove si dimostra come la fibrosi è una delle caratteristiche principali nella cardiomiopatia diabetica, i cuori dei topi diabetici evidenziano una maggiore deposizione di collagene. È interessante notare che la somministrazione di pargilina ha impedito questa alterazione, suggerendo che l'attività MAO rivesta un ruolo cruciale nella progressione della fibrosi in questi animali. Al fine di determinare se la fibrosi MAO-mediata sia dovuta al rilascio di fattori pro-infiammatori e pro-fibrotici da mastociti cardiaci, abbiamo valutato la loro degranulazione. Abbiamo osservato che, la degranulazione dei mastociti è aumentata di quasi 2 volte nei cuori diabetici rispetto ai topi di controllo. L’inibizione MAO ha completamente bloccato l'attivazione dei mastociti nei topi diabetici. Questi dati indicano un ruolo completamente nuovo di questi flavoenzimi nell'attivare mastociti cardiaci alla base del rimodellamento della matrice extracellulare, nella fibrosi e in ultima analisi, nella disfunzione del ventricolo sinistro (LV) in T1D.
Complessivamente, questi risultati dimostrano non solo come le MAO contribuisca alla formazione di ROS e alla disfunzione mitocondriale indotta da HG e dall’infiammazione, ma anche che queste specie reattive perturbano la funzione dell’ER e portano all’attivazione dell’UPR. Inoltre, abbiamo dimostrato come questi flavoenzimi svolgano un ruolo importante nella formazione di un circolo vizioso tra stress ossidativo e infiammazione, che è probabilmente la causa della fibrosi cardiaca e della disfunzione diastolica ventricolare sinistra nei topi diabetici. Gli inibitori MAO sono clinicamente disponibili e vengono utilizzati per il trattamento di diverse malattie neurologiche e neurodegenerative. I risultati del nostro studio suggeriscono come l'inibizione MAO potrebbe essere una strategia terapeutica promettente anche per il trattamento delle complicazioni cardiovascolari nel diabete.

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Tipo di EPrint:Tesi di dottorato
Relatore:Di Lisa, Fabio
Correlatore:Di Lisa, Fabio - Kaludercic, Nina
Dottorato (corsi e scuole):Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:30 Gennaio 2017
Anno di Pubblicazione:30 Gennaio 2017
Parole chiave (italiano / inglese):diabetic cardiomyopathy, endoplasmic reticulum, inflammation, mitochondria, monoamine oxidases
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:10126
Depositato il:20 Nov 2017 12:11
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