Valerio, Vincenza (2021) Identification of molecular mechanisms involved in the pathogenesis and progression of aortic valve stenosis for the discovery of new drug targets. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: Identification of molecular mechanisms involved in the pathogenesis and progression of aortic valve stenosis for the discovery of new drug targets
Creators:
CreatorsEmail
Valerio, Vincenzavincenza.valerio@gmail.com
Date: 10 December 2021
Number of Pages: 152
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Clinica e Chirurgia
Dottorato: Terapie avanzate biomediche e chirurgiche
Ciclo di dottorato: 34
Coordinatore del Corso di dottorato:
nomeemail
Di Minno, Giovannidiminno@unina.it
Tutor:
nomeemail
Di Minno, GiovanniUNSPECIFIED
Date: 10 December 2021
Number of Pages: 152
Keywords: Aortic valve sclerosis, aortic valve stenosis, oxidative stress, Ciclophilin A, PCSK9, calcification
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/13 - Biologia applicata
Area 06 - Scienze mediche > MED/11 - Malattie dell'apparato cardiovascolare
Area 06 - Scienze mediche > MED/50 - Scienze tecniche mediche applicate
Date Deposited: 21 Dec 2021 13:32
Last Modified: 28 Feb 2024 11:38
URI: http://www.fedoa.unina.it/id/eprint/14318

Collection description

Calcific aortic valve stenosis (CAVS) is the most common heart valve pathological condition worldwide. CAVS is an age-related disease, with a prevalence of almost 3% in the general population over 65 years of age. The disease's natural history evolves from an initial asymptomatic phase characterized by a thickening of the leaflets bearing possible micro-calcifications and a preserved left ventricle (LV) outflow tract still. This condition, known as aortic valve sclerosis (AVSc), has a prevalence of about 30% in adults older than 65 years of age. About 10% of these cases morph into aortic stenosis (AS), displaying massive calcifications and overt hemodynamic impairment. The only therapeutic option available for AS patients is either surgery or transcatheter aortic valve replacement. As the identification of new risk factors for pre- and post-operative mortality appears to be a central issue for ensuring high quality results in risk assessment systems, we first focused our attention on secondary prevention by identifying new risk factors. We have showed that the presence of AVSc, is a predictor of short- and long-term mortality in patients with overt atherosclerosis. Moreover, a deep understanding of CAVS pathogenic mechanisms would pave the way to new treatment opportunities and reduce its socioeconomic burden. To this end, we first focused on the study of endothelial dysfunction, an unavoidable step in CAVS’ onset. In particular, by studying damage to the endothelial cells that make up the aortic valve, we were able to test and apply innovative technologies by carrying out miRNA screening. This screening allowed us to classify endothelial cells isolated from bicuspid valves as more susceptible to damage due to oxidative stress. Continuing to study oxidative stress in endothelial cells, our results showed that treatment with Nacetyl-cysteine, a known antioxidant, can reduce aortic valve calcification, leading us to consider the potential use of antioxidant drugs in the primary prevention of this disease. Finally, we directed our attenction on molecular mechanisms involved in valve interstitial cells calcification. In particular, our study, revealed that Cyclophilin A and PCSK9 are causally involved in the pathogenesis of CAVS, identifying them as possible new drug targets.

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