title: Loss of p27 phosphorylation at Ser10 accelerates early atherogenesis by promoting leukocyte recruitment via RhoA/ROCK.
abstract: Reduced phosphorylation of the tumor suppressor p27(Kip1) (p27) at serine 10 (Ser10) is a hallmark of advanced human and mouse atherosclerosis. Apolipoprotein E-null mice defective for this posttranslational modification (apoE(-/-)p27Ser10Ala) exhibited increased atherosclerosis burden at late disease states. Here, we investigated the regulation of p27 phosphorylation in Ser10 at the very initial stages of atherosclerosis and its impact on endothelial-leukocyte interaction and early plaque formation. Hypercholesterolemia in fat-fed apoE(-/-) mice is associated with a rapid downregulation of p27-phospho-Ser10 in primary endothelial cells (ECs) and in aorta prior to the development of macroscopically-visible lesions. We find that lack of p27 phosphorylation at Ser10 enhances the expression of adhesion molecules in aorta of apoE(-/-) mice and ECs, and augments endothelial-leukocyte interactions and leukocyte recruitment in vivo. These effects correlated with increased RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signaling in ECs, and inhibition of this pathway with fasudil reduced leukocyte-EC interactions to control levels in the microvasculature of p27Ser10Ala mice. Moreover, apoE(-/-)p27Ser10Ala mice displayed increased leukocyte recruitment and homing to atherosusceptible arteries and augmented early plaque development, which could be blunted with fasudil. In conclusion, our studies demonstrate a very rapid reduction in p27-phospho-Ser10 levels at the onset of atherogenesis, which contributes to early plaque build-up through RhoA/ROCK-induced integrin expression in ECs and enhanced leukocyte recruitment.
authors.affiliation: Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Molina-Sánchez
authors.affiliation: Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Chèvre
authors.affiliation: Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rius
authors.affiliation: Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Fuster
authors.affiliation: Laboratory of Molecular and Genetic Cardiovascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. Electronic address: vandres@cnic.es.
authors.forename: V
authors.initials: V
authors.lastname: Andrés
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004032:Diet; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D019010:Vascular Cell Adhesion Molecule-1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010768:Phosphoserine; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Atherosclerosis; Endothelial cell; Leukocyte recruitment; RhoA; p27