PI3K p110γ Deletion Attenuates Murine Atherosclerosis by Reducing Macrophage Proliferation but Not Polarization or Apoptosis in Lesions

被引：15

作者：

Zotes, Teresa M. ^{[1
]}

Arias, Cristina F. ^{[1
]}

Fuster, Jose J. ^{[2
]}

Spada, Roberto ^{[1
]}

Perez-Yaguee, Sonia ^{[1
]}

Hirsch, Emilio ^{[3
]}

Wymann, Matthias ^{[4
]}

Carrera, Ana C. ^{[1
]}

Andres, Vicente ^{[2
]}

Barber, Domingo F. ^{[1
]}

机构：

[1] CSIC, CNB, Dept Immunol & Oncol, Madrid, Spain

[2] CNIC, Dept Epidemiol Atherothrombosis & Imaging, Madrid, Spain

[3] Univ Turin, Dept Genet Biol & Biochem, Ctr Mol Biotechnol, Turin, Italy

[4] Univ Basel, Dept Clin & Biol Sci, Inst Biochem & Genet, Basel, Switzerland

来源：

PLOS ONE | 2013年 / 8卷 / 08期

关键词：

COLONY-STIMULATING FACTOR; PHOSPHOINOSITIDE 3-KINASE GAMMA; REGULATORY T-CELLS; PHOSPHATIDYLINOSITOL; 3-KINASE; HUMAN MONOCYTES; FACTOR-I; ACTIVATION; KINASE; EXPRESSION; GRANULOCYTE;

D O I：

10.1371/journal.pone.0072674

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Atherosclerosis is an inflammatory disease regulated by infiltrating monocytes and T cells, among other cell types. Macrophage recruitment to atherosclerotic lesions is controlled by monocyte infiltration into plaques. Once in the lesion, macrophage proliferation in situ, apoptosis, and differentiation to an inflammatory (M1) or anti-inflammatory phenotype (M2) are involved in progression to advanced atherosclerotic lesions. We studied the role of phosphoinositol-3-kinase (PI3K) p110 gamma in the regulation of in situ apoptosis, macrophage proliferation and polarization towards M1 or M2 phenotypes in atherosclerotic lesions. We analyzed atherosclerosis development in LDLR(-/-)p110 gamma(+/-) and LDLR(-/-)p110 gamma(-/-) mice, and performed expression and functional assays in tissues and primary cells from these and from p110 gamma(+/-) and p110 gamma(-/-) mice. Lack of p110 gamma in LDLR-/- mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR(-/-)p110 gamma(-/-) mice were smaller than in LDLR(-/-)p110 gamma(+/-) controls, which coincided with decreased macrophage proliferation in LDLR(-/-)p110 gamma(-/-) mouse lesions. This proliferation defect was also observed in p110 gamma(-/-) bone marrow-derived macrophages (BMM) stimulated with macrophage colony-stimulating factor (M-CSF), and was associated with higher intracellular cyclic adenosine monophosphate (cAMP) levels. In contrast, T cell proliferation was unaffected in LDLR(-/-)p110 gamma(-/-) mice. Moreover, p110 gamma deficiency did not affect macrophage polarization towards the M1 or M2 phenotypes or apoptosis in atherosclerotic plaques, or polarization in cultured BMM. Our results suggest that higher cAMP levels and the ensuing inhibition of macrophage proliferation contribute to atheroprotection in LDLR-/- mice lacking p110 gamma. Nonetheless, p110 gamma deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation.

引用

页数：10

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[1] Phosphoinositide 3-kinase γ participates in T cell receptor-induced T cell activation [J].