2026-06-14T03:37:27Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/76562024-09-27T08:14:04Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Fuster, Jose J.
author
González-Navarro, Herminia
author
Vinué, Angela
author
Molina-Sanchez, Pedro
author
Andres-Manzano, Maria J.
author
Nakayama, Keiichi I
author
Nakayama, Keiko
author
Diez-Juan, Antonio
author
Bernad, Antonio
author
Rodriguez, Cristina
author
Martinez-Gonzalez, Jose
author
Andres, Vicente
funder
Ministerio de Ciencia e Innovación (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Instituto de Salud Carlos III
funder
Fundación Ramón Areces
funder
Fundación ProCNIC
2019-05-23T07:44:48Z
2019-05-23T07:44:48Z
2011-11
Arterioscler Thromb Vasc Biol. 2011; 31(11):2455-63
10.1161/ATVBAHA.111.235580
1524-4636
1079-5642
Arteriosclerosis, thrombosis, and vascular biology
21885849
http://hdl.handle.net/20.500.12105/7656
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.
eng
Deficient p27 phosphorylation at serine 10 increases macrophage foam cell formation and aggravates atherosclerosis through a proliferation-independent mechanism
journal article
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Deficientp27PhosphorylationSerine_2011_SupplementaryMaterial.pdf
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Deficientp27PhosphorylationSerine_2011_SupplementaryMaterial.pdf.txt
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