title: Novel small leucine-rich repeat protein podocan is a negative regulator of migration and proliferation of smooth muscle cells, modulates neointima formation, and is expressed in human atheroma.
abstract: BACKGROUND
  Smooth muscle cell (SMC) migration and proliferation critically influence the clinical course of vascular disease. We tested the effect of the novel small leucine-rich repeat protein podocan on SMC migration and proliferation using a podocan-deficient mouse in combination with a model of arterial injury and aortic explant SMC culture. In addition, we examined the effect of overexpression of the human form of podocan on human SMCs and tested for podocan expression in human atherosclerosis. In all these conditions, we concomitantly evaluated the Wnt-TCF (T-cell factor) pathway.
  
  
  RESULTS
  Podocan was strongly and selectively expressed in arteries of wild-type mice after injury. Podocan-deficient mice showed increased arterial lesion formation compared with wild-type littermates in response to injury (P<0.05). Also, SMC proliferation was increased in arteries of podocan-deficient mice compared with wild-type (P<0.05). In vitro, migration and proliferation were increased in podocan-deficient SMCs and were normalized by transfection with the wild-type podocan gene (P<0.05). In addition, upregulation of the Wnt-TCF pathway was found in SMCs of podocan-deficient mice both in vitro and in vivo. On the other hand, podocan overexpression in human SMCs significantly reduced SMC migration and proliferation, inhibiting the Wnt-TCF pathway. Podocan and a Wnt-TCF pathway marker were differently expressed in human coronary restenotic versus primary lesions.
  
  
  CONCLUSIONS
  Podocan appears to be a potent negative regulator of the migration and proliferation of both murine and human SMCs. The lack of podocan results in excessive arterial repair and prolonged SMC proliferation, which likely is mediated by the Wnt-TCF pathway.
authors.affiliation: Departments of Medicine and Cardiology, Mount Sinai School of Medicine, New York, NY (R.H., L.H., W.S.S., C.G., P.T., V.F., J.J.B.); Department of Cardiology, Elisabeth Klinikum, Schmalkalden, Germany (G.B.); Department of Medicine, Duke University, Durham, NC (M.E.K.); and Department of Medicine, Baylor College of Medicine, Houston, TX (P.E.K.).
authors.forename: Randolph
authors.initials: R
authors.lastname: Hutter
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Walter S
authors.initials: WS
authors.lastname: Speidl
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.forename: Paul
authors.initials: P
authors.lastname: Trubin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bauriedel
authors.forename: Mary E
authors.initials: ME
authors.lastname: Klotman
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
authors.forename: Paul E
authors.initials: PE
authors.lastname: Klotman
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology* / Q000502:physiology; D058426:Neointima / Q000473:pathology* / Q000503:physiopathology*; D058226:Plaque, Atherosclerotic / Q000473:pathology* / Q000503:physiopathology; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C477527:PODN protein, human
keywords: arteries; cell movement; cell proliferation; extracellular matrix; myocytes, smooth muscle
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