Article

High Expression of the Pi-Transporter SLC20A1/Pit1 in Calcific Aortic Valve Disease Promotes Mineralization through Regulation of Akt-1

Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec, Canada.
PLoS ONE (Impact Factor: 3.53). 01/2013; 8(1):e53393. DOI: 10.1371/journal.pone.0053393
Source: PubMed

ABSTRACT The regulation of phosphate (Pi) handling is crucial during calcification of the aortic valve. Gene profiling of Pi transporters revealed that VIC culture expresses SLC201A1/Pit1 and SLC20A2/Pit2. On exposure to a mineralizing medium (2 mM Pi), the expression of Pi transporters in VIC culture is increased several folds, with the highest magnitude for SLC20A1. By using siRNAs, we established that silencing SLC20A1 significantly reduced Pi-induced mineralization of VICs. In human pathological specimens, we found that the expression of SCL20A1 was increased in CAVD tissues compared to control non-mineralized aortic valves. Treatment of VIC culture with Pi promoted the loss of mitochondrial membrane potential (ΔΨm) and cytochrome c release within the cytosol, leading to apoptosis. Inhibition of Pi transporters with phosphonoformic acid (PFA) prevented Pi-mediated apoptosis of VICs. Moreover, we discovered that the level of the Akt-1 transcript is diminished in CAVD tissues compared with control valves. Accordingly, treatment with Pi caused a reduction of the Akt-1 transcript in VIC culture, and treatment with PFA or siRNA against SLC20A1 restored the level of Akt-1. Overexpression of Akt-1 (pCMVAkt-1) prevented both Pi-induced apoptosis and mineralization of VIC culture. These results strongly suggest that overexpression of SLC20A1 promotes apoptosis and mineralization by altering the level of Akt-1.

0 Followers
 · 
86 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although various osteogenic inducers contribute to the calcification of human aortic valve interstitial cells, the cellular origin of calcification remains unclear. We immunohistochemically investigated the cellular origin of valve calcification using enzymatically isolated cells from both calcified and non-calcified human aortic valve specimens. CD73-, 90-, and 105-positive and CD45-negative mesenchymal stem-like cells (MSLCs) were isolated from both types of valve specimens using fluorescence-activated cell sorting. MSLCs were further sorted into CD34-negative and -positive cells. Compared with CD34-positive cells, CD34-negative MSLCs were significantly more sensitive to high inorganic phosphate (3.2 mM), calcifying easily in response. Furthermore, immunohistochemical staining showed that significantly higher numbers (∼7-9-fold) of CD34-negative compared with CD34-positive MSLCs were localized in calcified aortic valve specimens obtained from calcified aortic stenosis patients. These results suggest that CD34-negative MSLCs are responsible for calcification of the aortic valve.
    Biochemical and Biophysical Research Communications 10/2013; 440(4). DOI:10.1016/j.bbrc.2013.10.003 · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Les complications cardiovasculaires (CCV) sont les causes les plus fréquentes de mortalité chez les patients ayant le diabète de type 2 (DT2). Cependant, les déterminants physiopathologiques et les mécanismes moléculaires impliqués dans la progression des CCV liées au DT2 sont mal compris. Nous avons entrepris de cerner quelques déterminants génétiques et cliniques des CCV par une approche multidisciplinaire unique impliquant des investigateurs canadiens et finlandais. Nous étudions les nouveaux modèles animaux combinant l’athérosclérose, l’obésité induite par l’alimentation et le DT2 pour comprendre les bases moléculaires des CCV du DT2 lié à l’obésité. Nous menons également des études cliniques pour cerner les principaux déterminants des CCV chez les patients ayant le DT2 et pour déterminer si un programme de modification du mode de vie ciblant la perte de tissu adipeux viscéral et de graisse ectopique pourrait être associée à des avantages cliniques chez ces patients. Ensemble, nous croyons fermement que nous pourrons combler certaines lacunes en matière de compréhension de la pathogenèse des CCV liées au DT2 et trouver de nouvelles cibles thérapeutiques, et nous espérons que ces nouvelles connaissances pourront mener à l’élaboration d’interventions cliniques efficaces destinées à réduire de manière optimale le risque cardiovasculaire chez les sujets ayant le DT2.
    Canadian Journal of Diabetes 10/2013; 37(5):351–358. DOI:10.1016/j.jcjd.2013.08.262 · 0.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several clinical studies reported an increased prevalence and accelerated progression of aortic valve calcification among patients with end-stage renal disease when compared with subjects with normal kidney function. Recently, mechanisms of calcific valve degeneration have been further elucidated and many of the pathways involved could be amplified in patients with decreased renal function. In particular, calcium-phosphate balance, MGP metabolism, OPG/RANK/RANKL triad, fetuin-A mineral complexes and FGF-23/Klotho axis have been shown to be impaired among patients with advanced chronic kidney disease and could play a role during vascular/valve calcification. The scope of the present review is to summarize the clinical data and the pathophysiological mechanisms potentially involved in the link between renal function decline and the progression of aortic valve disease.
    Nephrology Dialysis Transplantation 10/2013; DOI:10.1093/ndt/gft310 · 3.49 Impact Factor