PI3K p110c Deletion Attenuates Murine Atherosclerosis by Reducing Macrophage Proliferation but Not Polarization

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) p110c in the regulation of in situ apoptosis, macrophage proliferation and polarization towards M1 or M2 phenotypes in atherosclerotic lesions. We analyzed atherosclerosis development in LDLR2/2p110c+/2 and LDLR2/2p110c2/2 mice, and performed expression and functional assays in tissues and primary cells from these and from p110c+/2 and p110c2/2 mice. Lack of p110c in LDLR2/2 mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR2/2p110c2/2 mice were smaller than in LDLR2/2p110c+/2 controls, which coincided with decreased macrophage proliferation in LDLR2/ 2p110c2/2 mouse lesions. This proliferation defect was also observed in p110c2/2 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 LDLR2/2p110c2/2 mice. Moreover, p110c deficiency did not affect macrophage polarization towards the M1 or M2 phenotypes or apoptosis i