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Rattazzi, Marcello (2009) Contribution of Interstitial Valve Cells to Aortic Valve Calcification. [Ph.D. thesis]

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Abstract (english)

Background. The traditional view of aortic valve calcification as a slow, ineluctable event has been recently questioned by evidence showing the importance of a balance between promoting and inhibiting factors, and the relevance of osteogenic cellular-driven processes. The aortic valve leaflets are comprised of a heterogeneous population of interstitial cells (VIC) whose specific contribution to the degenerating valve has not been defined yet.
Aim. The major aim is to identify and describe the phenotypic characteristics of a subpopulation of aortic VIC able to acquire a pro-calcific profile when exposed to pathological stimuli (such as endotoxin [LPS] and inorganic phosphate [Pi]).
Methods and Results. Explants-derived primary bovine VIC (BVIC) were cloned by a limited dilution technique. Characterization of BVIC clones was performed by morphological and functional as well as immunophenotyping using markers specific for mesenchymal cells, smooth muscle (SM) cell lineage, endothelial cells, hematopoietic cells, and bone formation process. Among the 40 BVIC clones obtained we selected four clones, morphologically representative of the isolated populations, which displayed different growth pattern and immunophenotype. Both uncloned and cloned cell populations grown on plastics did not show a spontaneous tendency for calcification in the standard medium and were, hence, treated with different combinations of LPS (100 ng/ml) and Pi (2.4 mmol/L, final concentration) for 12 days. Uncloned BVIC showed a progressive increase of alkaline phosphatase (ALP) activity after treatment with LPS that resulted in calcium deposition after addition of Pi. Among the clones, only Clone 1 (fibroblast-like phenotype) showed relevant increase in ALP after LPS treatment, which was paralleled by an increased osteocalcin (OC) expression and prevention of smooth muscle (SM) ??actin (SMA) accumulation, as demonstrated by western blotting and cytofluorimetry analysis. The same treatment had no effect on Clone 4 cells that showed a more stable SM cell-like phenotype. Despite ALP activity and OC increase Clone 1 cells did not undergo calcium deposition after treatment with LPS in long-term culture supplemented with Pi. However, mineralization was observed in co-culture of Clone 1 and Clone 4 treated with LPS plus Pi. Moreover, when cells of Clone 1 were grown on type-I collagen sponges and treated with Pi alone or LPS plus Pi for 12 days we observed an extensive mineralization of the collagen-matrix. Instead, only modest calcium deposition was observed in collagen scaffolds seeded with Clone 4 treated in the same way. A high degree of apoptosis was documented in Clone 1 cells seeded in the collagen scaffolds and treated with LPS plus Pi. No apoptotic degeneration was observed in Clone 4 cells. The proteomic analysis of the cytosolic fraction of Clone 1 cells allowed the identification of 34 proteins which levels of expression were modified with the acquisition the pro-calcific profile. Among these proteins we documented a significant decrease in the expression of antioxidant proteins, such as superoxide dismutase [Cu-Zn] and thioredoxin, together with a downregulation in the level of dimethylarginine dimethylaminohydrolase (DDAH), an intracellular enzyme that degrades asymmetric dimethylarginine (ADMA) (a nitric oxide synthase inhibitor [NOS]). In line with these findings we observed that LPS treatment of Clone 1 cells was accompanied by increased reactive oxygen species (ROS) production.
Conclusion. The results of this study demonstrate that BVIC clonal subpopulations are endowed with different calcifying potential when stimulated with the same pathogenic factors. In particular, we identified a specific BVIC subset harbouring a fibroblast-like phenotype that express osteogenic markers and promote collagen-matrix calcification in response to endotoxin and elevated phosphate levels.

Abstract (italian)

Introduzione. Tradizionalmente la calcificazione valvolare aortica viene considerata un processo distrofico, ad evoluzione lenta e non modificabile. Tale visione è stata recentemente messa in discussione da evidenze che sottolineano l’importanza, nel corso della calcificazione vascolare, di un bilanciamento fra fattori promuoventi ed inibenti, nonché del ruolo svolto da processi cellulo-mediati. I lembi valvolari aortici sono popolati da cellule interstiziali valvolari (VIC) fenotipicamente eterogenee, il cui contributo specifico nel corso dei processi degenerativi della valvola è solo parzialmente conosciuto.
Scopo. Scopo del presente studio è quello di ricercare e caratterizzare una sottopopolazione aortica di VIC in grado di acquisire un fenotipo pro-calcifico in seguito ad esposizione a fattori patogeni (quali endotossina [LPS] e fosfato inorganico [Pi]).
Metodi e Risultati. VIC ottenute da espianti di valvole aortiche bovine (BVIC) sono state sottoposte ad un processo di clonazione, mediante tecnica di diluizione limite. I cloni di BVIC sono stati caratterizzati sotto il profilo morfologico ed immunofenotipico mediante l’utilizzo di marcatori tipici per cellule mesenchimali, cellule muscolari lisce (SMC), cellule endoteliali, cellule ematopoietiche e cellule di derivazione ossea. Fra i 40 cloni di BVIC ottenuti sono stati selezionati 4 cloni, morfologicamente rappresentativi delle diverse popolazioni isolate, che mostravano diverse caratteristiche di crescita e di profilo immunofenotipico. Sia la popolazione cellulare di VIC non clonate che i cloni non mostravano la tendenza a fenomeni spontanei di calcificazione in vitro. Le cellule sono state quindi trattate con diverse combinazioni di LPS (100 ng/ml) e Pi (2.4 mmol/L concentrazione finale) per 12 giorni. La popolazione non clonale di BVIC ha mostrato un progressivo incremento nei livelli di espressione della fosfatasi alcalina (ALP) dopo trattamento con LPS, mentre la deposizione di calcio è stata osservata solo nelle cellule trattate con la combinazione di LPS e Pi. Fra i diversi cloni solo il Clone 1 (fenotipo simil-fibroblasto) ha mostrato un significativo incremento nei livelli di espressione dell’ALP. Tale incremento si accompagnava ad un’aumentata espressione di osteocalcina (OC) e ridotto accumulo di ?-actina muscolare liscia (SMA), come documentato da studi in western blotting e citofluorimetria. Il trattamento con LPS non è stato in grado di indurre modifiche simili nel profilo fenotipico del Clone 4 (fenotipo muscolare liscio differenziato). Nonostante il significativo incremento nell’espressione di ALP ed OC, il Clone 1 non ha prodotto fenomeni di calcificazione della matrice dopo trattamento con la combinazione di LPS ed Pi. Tuttavia, aspetti di calcificazione sono stati osservati in esperimenti di co-coltura del Clone 1 e Clone 4, quando trattati con la combinazione di LPS e Pi. Inoltre, dopo semina su spugne di collagene di tipo I, il Clone 1 si è dimostrato in grado di produrre estesi fenomeni di calcificazione della matrice, in seguito a trattamento per 12 giorni con LPS e Pi. Tale combinazione ha indotto solo minimi aspetti di calcificazione nella matrice di collagene popolata dal Clone 4. Fenomeni apoptotici sono stati osservati nel Clone 1 seminato nelle spugne di collagene e trattato con LPS e Pi. Viceversa, nel caso del Clone 4 non sono stati documentati aspetti apoptotici. L’analisi proteomica della frazione citosolica del Clone 1 ha permesso di identificare 34 proteine i cui livelli di espressione si modificano con l’acquisizione del profilo pro-calcifico. Fra queste proteine è stata documentata una significativa riduzione nei livelli di molecole antiossidanti, come la superossido dismutasi [Cu-Zn] e la tioredoxina. Un significativo decremento è stato osservato anche per i livelli di dimetilarginina dimetilaminoidrolase (DDAH), un enzima intracellulare che degrada la dimetilarginina asimmetrica (ADMA) (inibitore dell’ossido nitrico sintetasi [NOS]). In linea con questi dati è stato osservato un aumento della produzione di specie reattive dell’ossigeno (ROS) da parte del Clone 1 trattato con LPS.
Conclusioni. I risultati di questo lavoro dimostrano che le popolazioni clonali di BVIC sono dotate di un diverso potenziale pro-calcifico quando stimolate con uno stesso fattore patogeno. In particolare, è stata identificata una specifica sottopopolazione di BVIC, caratterizzata da un profilo fenotipico simil-fibroblasto, che si è dimostrata in grado di esprimere marcatori osteogenici e di calcificare matrice di collagene, in risposta a trattamento con endotossina ed alti livelli di fosfato inorganico.

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EPrint type:Ph.D. thesis
Tutor:Pauletto, Paolo
Ph.D. course:Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:02 February 2009
Anno di Pubblicazione:02 February 2009
Key Words:stenosi aortica, calcificazione, cellule interstiziali valvolari
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Medico Diagnostiche e Terapie Speciali
Codice ID:1368
Depositato il:02 Feb 2009
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