Abstract
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) p110γ 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−/−p110γ+/− and LDLR−/−p110γ−/− mice, and performed expression and functional assays in tissues and primary cells from these and from p110γ+/− and p110γ−/− mice. Lack of p110γ in LDLR−/− mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR−/−p110γ−/− mice were smaller than in LDLR−/−p110γ+/− controls, which coincided with decreased macrophage proliferation in LDLR−/−p110γ−/− mouse lesions. This proliferation defect was also observed in p110γ−/− 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−/−p110γ−/− mice. Moreover, p110γ 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 p110γ. Nonetheless, p110γ deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation.
Highlights
Atherosclerosis has traditionally been considered a disorder of cholesterol metabolism that results in lipid accumulation in the arterial wall, provoking artery wall thickening
In the disease, oxidized low-density lipoproteins that have accumulated in the intima activate endothelial cells; these secrete a number of pro-inflammatory molecules that recruit specific leukocyte types into the artery wall [3]
Coincident with the increased cyclic adenosine monophosphate (cAMP) detected in the protein lysates, we found higher basal p-cAMP response element binding protein (CREB) levels in LDLR2/2p110c2/2 mouse bone marrow-derived macrophages (BMM) (Figure 4D)
Summary
Atherosclerosis has traditionally been considered a disorder of cholesterol metabolism that results in lipid accumulation in the arterial wall, provoking artery wall thickening It shares features of chronic inflammatory diseases, such as infiltration of activated immune cells into the artery wall [1], [2]. Macrophage and T lymphocyte activation lead to the release of additional mediators, including cytokines, chemokines and growth factors [1], [8]. This chronic inflammatory environment promotes progression of early lesions (or fatty streaks) to complex lesions (or advanced plaques) that protrude into the arterial lumen and can trigger atherothrombotic vascular disease [1], [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
