title: Deficient p27 phosphorylation at serine 10 increases macrophage foam cell formation and aggravates atherosclerosis through a proliferation-independent mechanism.
abstract: OBJECTIVE
  Genetic ablation of the growth suppressor p27(Kip1) (p27) in the mouse aggravates atherosclerosis coinciding with enhanced arterial cell proliferation. However, it is unknown whether molecular mechanisms that limit p27's protective function contribute to atherosclerosis development and whether p27 exerts proliferation-independent activities in the arterial wall. This study aims to provide insight into both questions by investigating the role in atherosclerosis of p27 phosphorylation at serine 10 (p27-phospho-Ser10), a major posttranslational modification of this protein.
  
  
  RESULTS
  Immunoblotting studies revealed a marked reduction in p27-phospho-Ser10 in atherosclerotic arteries from apolipoprotein E-null mice, and expression of the nonphosphorylatable mutant p27Ser10Ala, either global or restricted to bone marrow, accelerated atherosclerosis. p27Ser10Ala expression did not affect cell proliferation in early and advanced atheroma but activated RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signaling and promoted macrophage foam cell formation in a ROCK-dependent manner. Supporting the clinical relevance of these findings, human atherosclerotic coronary arteries exhibited a prominent reduction in p27-phospho-Ser10 and increased ezrin/radixin/moesin protein phosphorylation, a marker of RhoA/ROCK activation.
  
  
  CONCLUSIONS
  Scarce phosphorylation of p27 at Ser10 is a hallmark of human and mouse atherosclerosis and promotes disease progression in mice. This proatherogenic effect is mediated by a proliferation-independent mechanism that involves augmented foam cell formation owing to increased RhoA/ROCK activity. These findings unveil a new atheroprotective action of p27 and identify p27-phospho-Ser10 as an attractive target for the treatment of atherosclerosis.
authors: Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: José J
authors: JJ
authors: Fuster
authors: Herminia
authors: H
authors: González-Navarro
authors: Angela
authors: A
authors: Vinué
authors: Pedro
authors: P
authors: Molina-Sànchez
authors: Maria J
authors: MJ
authors: Andrés-Manzano
authors: Keiichi I
authors: KI
authors: Nakayama
authors: Keiko
authors: K
authors: Nakayama
authors: Antonio
authors: A
authors: Díez-Juan
authors: Antonio
authors: A
authors: Bernad
authors: Cristina
authors: C
authors: Rodríguez
authors: José
authors: J
authors: Martínez-González
authors: Vicente
authors: V
authors: Andrés
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005487:Foam Cells / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
chemical_list: D001057:Apolipoproteins E; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012694:Serine; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein