TY - JOUR
T1 - Cyclophilin A inhibition as potential treatment of human aortic valve calcification
AU - Perrucci, Gianluca L.
AU - Songia, Paola
AU - Moschetta, Donato
AU - Barbagallo, Veronica A.
AU - Valerio, Vincenza
AU - Myasoedova, Veronika A.
AU - Alfieri, Valentina
AU - Massaiu, Ilaria
AU - Roberto, Maurizio
AU - Malešević, Miroslav
AU - Pompilio, Giulio
AU - Poggio, Paolo
N1 - Funding Information:
This work was supported by the Italian Ministry of Health funds (Ricerca Corrente: RC-2016-BIO34-2627243 ; RC-2019-CA1A-2755299 ; RC-2019-CA1E-2755807 ) and by Fondazione Gigi e Pupa Ferrari ONLUS ( FPF-14 ).
Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - Aortic valve stenosis (AS) is a pathological condition that affects about 3% of the population, representing the most common valve disease. The main clinical feature of AS is represented by the impaired leaflet motility, due to calcification, which leads to the left ventricular outflow tract obstruction during systole. The formation and accumulation of calcium nodules are driven by valve interstitial cells (VICs). Unfortunately, to date, the in vitro and in vivo studies were not sufficient to fully recapitulate all the pathological pathways involved in AS development, as well as to define a specific and effective pharmacological treatment for AS patients. Cyclophilin A (CyPA), the most important immunophilin and endogenous ligand of cyclosporine A (CsA), is strongly involved in several detrimental cardiovascular processes, such as calcification. To date, there are no data on the CyPA role in VIC-mediated calcification process of AS. Here, we aimed to identify the role of CyPA in AS by studying VIC calcification, in vitro. In this study, we found that (i) CyPA is up-regulated in stenotic valves of AS patients, (ii) pro-calcifying medium promotes CyPA secretion by VICs, (iii) in vitro treatment of VICs with exogenous CyPA strongly stimulates calcium deposition, and (iv) exogenous CyPA inhibition mediated by CsA analogue MM284 abolished in vitro calcium potential. Thus, CyPA represents a biological target that may act as a novel candidate in the detrimental AS development and its inhibition may provide a novel pharmacological approach for AS treatment.
AB - Aortic valve stenosis (AS) is a pathological condition that affects about 3% of the population, representing the most common valve disease. The main clinical feature of AS is represented by the impaired leaflet motility, due to calcification, which leads to the left ventricular outflow tract obstruction during systole. The formation and accumulation of calcium nodules are driven by valve interstitial cells (VICs). Unfortunately, to date, the in vitro and in vivo studies were not sufficient to fully recapitulate all the pathological pathways involved in AS development, as well as to define a specific and effective pharmacological treatment for AS patients. Cyclophilin A (CyPA), the most important immunophilin and endogenous ligand of cyclosporine A (CsA), is strongly involved in several detrimental cardiovascular processes, such as calcification. To date, there are no data on the CyPA role in VIC-mediated calcification process of AS. Here, we aimed to identify the role of CyPA in AS by studying VIC calcification, in vitro. In this study, we found that (i) CyPA is up-regulated in stenotic valves of AS patients, (ii) pro-calcifying medium promotes CyPA secretion by VICs, (iii) in vitro treatment of VICs with exogenous CyPA strongly stimulates calcium deposition, and (iv) exogenous CyPA inhibition mediated by CsA analogue MM284 abolished in vitro calcium potential. Thus, CyPA represents a biological target that may act as a novel candidate in the detrimental AS development and its inhibition may provide a novel pharmacological approach for AS treatment.
KW - Aortic valve stenosis
KW - Calcification
KW - Cyclophilin A
KW - Cyclosporin A analogue
KW - Pharmacological target
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U2 - 10.1016/j.phrs.2020.104888
DO - 10.1016/j.phrs.2020.104888
M3 - Article
C2 - 32434054
AN - SCOPUS:85085578364
VL - 158
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
M1 - 104888
ER -