| First Author | Zotes TM | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 8 | Pages | e72674 |
| PubMed ID | 23991137 | Mgi Jnum | J:204917 |
| Mgi Id | MGI:5543729 | Doi | 10.1371/journal.pone.0072674 |
| Citation | Zotes TM, et al. (2013) PI3K p110gamma deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions. PLoS One 8(8):e72674 |
| abstractText | 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) p110gamma 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(-/-)p110gamma(+/-) and LDLR(-/-)p110gamma(-/-) mice, and performed expression and functional assays in tissues and primary cells from these and from p110gamma(+/-) and p110gamma(-/-) mice. Lack of p110gamma in LDLR(-/-) mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR(-/-)p110gamma(-/-) mice were smaller than in LDLR(-/-)p110gamma(+/-) controls, which coincided with decreased macrophage proliferation in LDLR(-/-)p110gamma(-/-) mouse lesions. This proliferation defect was also observed in p110gamma(-/-) 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(-/-)p110gamma(-/-) mice. Moreover, p110gamma 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 p110gamma. Nonetheless, p110gamma deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation. |
