title: The bone morphogenetic protein antagonist gremlin promotes vascular smooth muscle cell apoptosis.
abstract: BACKGROUND
  Previous studies from our laboratory demonstrated that gremlin significantly increases vascular smooth muscle cell (VSMC) proliferation and migration. The present study investigates gremlin expression in the initial stages of rat carotid balloon injury and its effects on VSMC apoptosis.
  
  
  METHODS
  Gremlin mRNA expression was evaluated in rat carotids and cultured VSMCs by quantitative PCR. Apoptosis was analyzed in A7r5 cells and rabbit primary VSMCs following gremlin gene overexpression or silencing by chromatin morphology and caspase-3 activity.
  
  
  RESULTS
  Vascular injury promoted a significant decrease in gremlin mRNA levels. In addition, platelet-derived growth factor, angiotensin II and transforming growth factor (TGF)-beta1 promoted coordinated regulation of gremlin and bone morphogenetic protein (BMP)-4 expression in opposite directions according to the confluence status of VSMC culture. In A7r5 cells, gremlin overexpression was able to increase apoptosis, as demonstrated by chromatin morphology and caspase-3 activity, while BMP administration promoted opposite effects. Finally, in agreement with our results, gremlin gene silencing effectively suppressed apoptosis in A7r5 cells and rabbit VSMCs.
  
  
  CONCLUSIONS
  Gremlin is regulated by growth factors and vascular injury and is involved in modulation of VSMC apoptosis. Modifications of gremlin expression during vascular injury may contribute to the apoptosis resistance of VSMCs.
authors.affiliation: Albert Einstein Research and Education Institute, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Thiago Trovati
authors.initials: TT
authors.lastname: Maciel
authors.forename: Rosilene Santos
authors.initials: RS
authors.lastname: Melo
authors.forename: Alexandre Holthausen
authors.initials: AH
authors.lastname: Campos
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020212:Carotid Artery Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D016207:Cytokines; D004195:Disease Models, Animal; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011506:Proteins; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C525720:Bmp2 protein, rat; C525811:Bmp4 protein, rat; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C107276:Grem1 protein, rat; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; C505410:Casp3 protein, rat; D053148:Caspase 3