Pulmonary hypertension (PH) is a debilitating and often fatal condition with limited treatment options, ultimately leading to right heart failure and mortality. The pathogenesis of pulmonary hypertension is a complex interplay of various factors, including genetic, epigenetic, and environmental influences. MicroRNAs (miRNAs) are small non-coding RNA molecules that play a crucial role in post-transcriptional gene regulation. They typically consist of about 21 to 25 nucleotides in length. One of the fascinating aspects of miRNAs is their ability to regulate gene expression of various biological processes in a highly coordinated and complex manner. Changes in miRNAs expression rates can lead to several diseases, including PH. Lung transplantation represents the last resort for advanced parenchymal or vascular lung diseases. The current study recognizes the substantial value of lung tissue obtained from explanted lungs for fundamental research purposes. By investigating small samples of paraffin-embedded explanted lungs affected by both group 3 and group 1 pulmonary hypertension, the study aims to uncover shared pathogenic mechanisms between these two groups through a comparative analysis of the quantitative expression patterns of a panel of miRNAs among distinct groups. We considered miRNAs involved in pulmonary arterial endothelial disfunction and vascular remodeling: miR-140-5p, miR-24-1-5p, miR-103a-2-5p, miR-126-5p, miR-21-5p, miR-26a-5p, miR-20a-5p, miR-98-5p, miR-301a-5p, miR-17-5p, miR-92a-1-5p, miR-191-5p. Our study has demonstrated that miR-21 is down-regulated in patients with IPAH compared to patients with IPF and pulmonary hypertension. The role of miR-21 in relation to the findings of our study suggests that the higher expression of miR-21 in patients with group 3 PH may be justified by a greater hypoxic stimulus. Furthermore, the protective role on pulmonary vascular endothelium could account for the significantly lower values of PAPm observed in patients with group 3 PH compared to those with IPAH. Our other notable result of our study highlights a statistically significant difference in the expression of miR-26, which is upregulated in patients with IPAH compared to patients with group 3 pulmonary hypertension, as well as those with IPF and COPD. The overexpression of miR-26 in patients with IPAH may be correlated with impaired differentiation of pulmonary arterial smooth muscle cells, thus contributing to inhibited PASMC differentiation and the development of pulmonary vascular pathology.
L’ipertensione polmonare è una condizione debilitante e spesso fatale con opzioni di trattamento limitate, che porta a insufficienza cardiaca destra e infine a morte. La patogenesi dell’ipertensione polmonare è una complessa interazione di vari fattori, tra cui influenze genetiche, epigenetiche e ambientali. I microRNA (miRNA) sono piccole molecole di RNA non codificanti che svolgono un ruolo cruciale nella regolazione genica post-trascrizionale. Tipicamente sono costituiti da circa 21-25 nucleotidi di lunghezza. Uno degli aspetti affascinanti dei miRNA è la loro capacità di regolare l’espressione genica di vari processi biologici in modo altamente coordinato e complesso. I cambiamenti nei tassi di espressione dei miRNA possono portare a diverse malattie, inclusa l’ipertensione polmonare. Il trapianto polmonare rappresenta l’ultima risorsa per le malattie parenchimali o vascolari polmonari avanzate. Lo studio attuale riconosce il valore sostanziale del tessuto polmonare ottenuto dai polmoni espiantati per scopi di ricerca fondamentale. Analizzando piccoli campioni di polmoni espiantati inclusi in paraffina affetti da ipertensione polmonare sia di gruppo 3 che di gruppo 1, lo studio mira a scoprire i meccanismi patogenetici condivisi tra questi due gruppi attraverso un'analisi comparativa dei modelli di espressione quantitativa di un pannello di miRNA tra gruppi distinti. Abbiamo considerato i miRNA coinvolti nella disfunzione endoteliale arteriosa polmonare e nel rimodellamento vascolare: miR-140-5p, miR-24-1-5p, miR-103a-2-5p, miR-126-5p, miR-21-5p, miR-26a -5p, miR-20a-5p, miR-98-5p, miR-301a-5p, miR-17-5p, miR-92a-1-5p, miR-191-5p. Il nostro studio ha dimostrato che miR-21 è sottoregolato nei pazienti con ipertensione arteriosa polmonare idiopatica rispetto ai pazienti con fibrosi polmonare idiopatica e ipertensione polmonare. Il ruolo di miR-21 in relazione ai risultati del nostro studio suggerisce che la maggiore espressione di miR-21 nei pazienti con ipertensione polmonare di gruppo 3 può essere giustificata da un maggiore stimolo ipossico. Inoltre, il ruolo protettivo sull’endotelio vascolare polmonare potrebbe spiegare i valori significativamente più bassi di pressione arteriosa polmonare media osservati nei pazienti con ipertensione polmonare del gruppo 3 rispetto a quelli con ipertensione arteriosa polmonare idiopatica. L'altro risultato rilevante del nostro studio evidenzia una differenza statisticamente significativa nell'espressione di miR-26, che è sovraregolata nei pazienti con ipertensione arteriosa polmonare idipatica rispetto ai pazienti con ipertensione polmonare di gruppo 3, nonché a quelli con fibrosi polmonare idiopatica e broncopneumopatia cronica ostruttiva. La sovraespressione di miR-26 nei pazienti con ipertensione arteriosa idiopatica può essere correlata con una ridotta differenziazione delle cellule muscolari lisce dell'arteria polmonare, contribuendo così all'inibizione della differenziazione di queste cellule e allo sviluppo della patologia vascolare polmonare.
THE ROLE OF miRNAs IN PRE-CAPILLARY PULMONARY HYPERTENSION: A COMPARISON BETWEEN GROUP 1 AND GROUP 3
CAUSA, ELENA
2022/2023
Abstract
Pulmonary hypertension (PH) is a debilitating and often fatal condition with limited treatment options, ultimately leading to right heart failure and mortality. The pathogenesis of pulmonary hypertension is a complex interplay of various factors, including genetic, epigenetic, and environmental influences. MicroRNAs (miRNAs) are small non-coding RNA molecules that play a crucial role in post-transcriptional gene regulation. They typically consist of about 21 to 25 nucleotides in length. One of the fascinating aspects of miRNAs is their ability to regulate gene expression of various biological processes in a highly coordinated and complex manner. Changes in miRNAs expression rates can lead to several diseases, including PH. Lung transplantation represents the last resort for advanced parenchymal or vascular lung diseases. The current study recognizes the substantial value of lung tissue obtained from explanted lungs for fundamental research purposes. By investigating small samples of paraffin-embedded explanted lungs affected by both group 3 and group 1 pulmonary hypertension, the study aims to uncover shared pathogenic mechanisms between these two groups through a comparative analysis of the quantitative expression patterns of a panel of miRNAs among distinct groups. We considered miRNAs involved in pulmonary arterial endothelial disfunction and vascular remodeling: miR-140-5p, miR-24-1-5p, miR-103a-2-5p, miR-126-5p, miR-21-5p, miR-26a-5p, miR-20a-5p, miR-98-5p, miR-301a-5p, miR-17-5p, miR-92a-1-5p, miR-191-5p. Our study has demonstrated that miR-21 is down-regulated in patients with IPAH compared to patients with IPF and pulmonary hypertension. The role of miR-21 in relation to the findings of our study suggests that the higher expression of miR-21 in patients with group 3 PH may be justified by a greater hypoxic stimulus. Furthermore, the protective role on pulmonary vascular endothelium could account for the significantly lower values of PAPm observed in patients with group 3 PH compared to those with IPAH. Our other notable result of our study highlights a statistically significant difference in the expression of miR-26, which is upregulated in patients with IPAH compared to patients with group 3 pulmonary hypertension, as well as those with IPF and COPD. The overexpression of miR-26 in patients with IPAH may be correlated with impaired differentiation of pulmonary arterial smooth muscle cells, thus contributing to inhibited PASMC differentiation and the development of pulmonary vascular pathology.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/16501