title: Inorganic phosphate accelerates the migration of vascular smooth muscle cells: evidence for the involvement of miR-223.
abstract: BACKGROUND
  An elevated serum inorganic phosphate (Pi) level is a major risk factor for kidney disease and downstream vascular complications. We focused on the effect of Pi levels on human aortic vascular smooth muscle cells (VSMCs), with an emphasis on the role of microRNAs (miRNAs).
  
  
  RESULTS
  Exposure of human primary VSMCs in vitro to pathological levels of Pi increased calcification, migration rate and concomitantly reduced cell proliferation and the amount of the actin cytoskeleton. These changes were evidenced by significant downregulation of miRNA-143 (miR-143) and miR-145 and concomitant upregulation of their targets and key markers in synthetic VSMCs, such as Krüppel-like factors-4 and -5 and versican. Interestingly, we also found that miR-223 (a marker of muscle damage and a key factor in osteoclast differentiation) is expressed in VSMCs and is significantly upregulated in Pi-treated cells. Over-expressing miR-223 in VSMCs increased proliferation and markedly enhanced VSMC migration. Additionally, we found that the expression of two of the known miR-223 targets, Mef2c and RhoB, was highly reduced in Pi treated as well as miR-223 over-expressing VSMCs. To complement these in vitro findings, we also observed significant downregulation of miR-143 and miR-145 and upregulation of miR-223 in aorta samples collected from ApoE knock-out mice, which display vascular calcification.
  
  
  CONCLUSIONS
  Our results suggest that (i) high levels of Pi increase VSMC migration and calcification, (ii) altered expression levels of miR-223 could play a part in this process and (iii) miR-223 is a potential new biomarker of VSMC damage.
authors.affiliation: INSERM U1088, Amiens, France.
authors.forename: Ashraf Yusuf
authors.initials: AY
authors.lastname: Rangrez
authors.forename: Eléonore
authors.initials: E
authors.lastname: M'Baya-Moutoula
authors.forename: Valérie
authors.initials: V
authors.lastname: Metzinger-Le Meuth
authors.forename: Lucie
authors.initials: L
authors.lastname: Hénaut
authors.forename: Mohamed Seif el Islam
authors.initials: MS
authors.lastname: Djelouat
authors.forename: Joyce
authors.initials: J
authors.lastname: Benchitrit
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
authors.forename: Laurent
authors.initials: L
authors.lastname: Metzinger
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism* / Q000494:pharmacology; D061251:Primary Cell Culture; D015854:Up-Regulation / Q000187:drug effects; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism; D053675:Versicans / Q000235:genetics / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D051741:Kruppel-Like Transcription Factors; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors; D010710:Phosphates; D053675:Versicans; D020743:rhoB GTP-Binding Protein; C578040:MEF2C protein, human; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; C525067:MIR223, human; C508322:VCAN protein, human