Deficient p27 Phosphorylation at Serine 10 Increases Macrophage Foam Cell Formation and Aggravates Atherosclerosis Through a Proliferation-Independent Mechanism

6533b870fe1ef96bd12d075c

RESEARCH PRODUCT

Deficient p27 Phosphorylation at Serine 10 Increases Macrophage Foam Cell Formation and Aggravates Atherosclerosis Through a Proliferation-Independent Mechanism

Antonio Bernad Herminia González-navarro Herminia González-navarro Vicente Andrés Keiko Nakayama ÁNgela Vinué Pedro Molina-sánchez José J. Fuster José Martínez-gonzález María J. Andrés-manzano Keiichi I. Nakayama Antonio Díez-juan Cristina Rodríguez

subject

Male rho GTP-Binding Proteins RHOA Moesin Mice Apolipoproteins E Radixin Serine medicine Animals Humans Protein phosphorylation Phosphorylation Protein kinase A Cell Proliferation Foam cell Mice Knockout rho-Associated Kinases biology Arteries Atherosclerosis medicine.disease Cell biology Mice Inbred C57BL Disease Models Animal Atheroma Case-Control Studies Immunology Disease Progression biology.protein Phosphorylation Female rhoA GTP-Binding Protein Cardiology and Cardiovascular Medicine Cyclin-Dependent Kinase Inhibitor p27 Foam Cells Signal Transduction

description

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. METHODS AND 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. CONCLUSION: 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. This work was supported by grants from the Spanish Ministry of Science and Innovation and European Regional Development Fund (SAF2007-62110 and SAF2010-16044 to V.A.), Instituto de Salud Carlos III (RECAVA RD06/0014/0021 to V.A. and RD06/0014/ 0027 to J.M.-G.), and Fundacion Ramon Areces (to V.A.). Dr Fuster was supported by the CSIC-I3P predoctoral fellowship program cosponsored by the European Regional Development Fund. The Centro Nacional de Investigaciones Cardiovasculares is supported by the Spanish Ministry of Science and Innovation and the Fundacion Pro-CNIC. Sí

year	journal	country	edition	language
2011-11-01	Arteriosclerosis, Thrombosis, and Vascular Biology

https://doi.org/10.1161/atvbaha.111.235580