Deficient p27 phosphorylation at serine 10 increases macrophage foam cell formation and aggravates atherosclerosis through a proliferation-independent mechanism

José J. Fuster, Herminia González-Navarro, Angela Vinué, Pedro Molina-Sànchez, Maria J. Andrés-Manzano, Keiichi I. Nakayama, Keiko Nakayama, Antonio Díez-Juan, Antonio Bernad, Cristina Rodríguez, José Martínez-González, Vicente Andrés

研究成果: ジャーナルへの寄稿記事

14 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)2455-2463
ページ数9
ジャーナルArteriosclerosis, thrombosis, and vascular biology
31
発行部数11
DOI
出版物ステータス出版済み - 11 1 2011

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Foam Cells
Serine
Atherosclerosis
Macrophages
Phosphorylation
Cell Proliferation
rho-Associated Kinases
Apolipoproteins E
Atherosclerotic Plaques
Post Translational Protein Processing
Immunoblotting
Disease Progression
Coronary Vessels
Proteins
Arteries
Bone Marrow
Growth

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

Deficient p27 phosphorylation at serine 10 increases macrophage foam cell formation and aggravates atherosclerosis through a proliferation-independent mechanism. / Fuster, José J.; González-Navarro, Herminia; Vinué, Angela; Molina-Sànchez, Pedro; Andrés-Manzano, Maria J.; Nakayama, Keiichi I.; Nakayama, Keiko; Díez-Juan, Antonio; Bernad, Antonio; Rodríguez, Cristina; Martínez-González, José; Andrés, Vicente.

:: Arteriosclerosis, thrombosis, and vascular biology, 巻 31, 番号 11, 01.11.2011, p. 2455-2463.

研究成果: ジャーナルへの寄稿記事

Fuster, JJ, González-Navarro, H, Vinué, A, Molina-Sànchez, P, Andrés-Manzano, MJ, Nakayama, KI, Nakayama, K, Díez-Juan, A, Bernad, A, Rodríguez, C, Martínez-González, J & Andrés, V 2011, 'Deficient p27 phosphorylation at serine 10 increases macrophage foam cell formation and aggravates atherosclerosis through a proliferation-independent mechanism', Arteriosclerosis, thrombosis, and vascular biology, 巻. 31, 番号 11, pp. 2455-2463. https://doi.org/10.1161/ATVBAHA.111.235580
Fuster, José J. ; González-Navarro, Herminia ; Vinué, Angela ; Molina-Sànchez, Pedro ; Andrés-Manzano, Maria J. ; Nakayama, Keiichi I. ; Nakayama, Keiko ; Díez-Juan, Antonio ; Bernad, Antonio ; Rodríguez, Cristina ; Martínez-González, José ; Andrés, Vicente. / Deficient p27 phosphorylation at serine 10 increases macrophage foam cell formation and aggravates atherosclerosis through a proliferation-independent mechanism. :: Arteriosclerosis, thrombosis, and vascular biology. 2011 ; 巻 31, 番号 11. pp. 2455-2463.
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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. 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.",
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T1 - Deficient p27 phosphorylation at serine 10 increases macrophage foam cell formation and aggravates atherosclerosis through a proliferation-independent mechanism

AU - Fuster, José J.

AU - González-Navarro, Herminia

AU - Vinué, Angela

AU - Molina-Sànchez, Pedro

AU - Andrés-Manzano, Maria J.

AU - Nakayama, Keiichi I.

AU - Nakayama, Keiko

AU - Díez-Juan, Antonio

AU - Bernad, Antonio

AU - Rodríguez, Cristina

AU - Martínez-González, José

AU - Andrés, Vicente

PY - 2011/11/1

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N2 - 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.

AB - 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.

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