title: High expression of the Pi-transporter SLC20A1/Pit1 in calcific aortic valve disease promotes mineralization through regulation of Akt-1.
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.
authors: 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.
authors: Diala
authors: D
authors: El Husseini
authors: Marie-Chloé
authors: MC
authors: Boulanger
authors: Dominique
authors: D
authors: Fournier
authors: Ablajan
authors: A
authors: Mahmut
authors: Yohan
authors: Y
authors: Bossé
authors: Philippe
authors: P
authors: Pibarot
authors: Patrick
authors: P
authors: Mathieu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D000082882:Bicuspid Aortic Valve Disease; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006349:Heart Valve Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D010710:Phosphates; D034741:RNA, Small Interfering; C493586:SLC20A1 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt