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Protein Kinase C? Via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6Chi Cells Contributes to Atherosclerosis.

ABSTRACT: BACKGROUND:Although the role of thrombin in atherothrombosis is well studied, its role in the pathogenesis of diet-induced atherosclerosis is not known. METHODS:Using a mouse model of diet-induced atherosclerosis and molecular biological approaches, here we have explored the role of thrombin and its G protein-coupled receptor signaling in diet-induced atherosclerosis. RESULTS:In exploring the role of G protein-coupled receptor signaling in atherogenesis, we found that thrombin triggers foam cell formation via inducing CD36 expression, and these events require Par1-mediated G?12-Pyk2-Gab1-protein kinase C (PKC)?-dependent ATF2 activation. Genetic deletion of PKC? in apolipoprotein E (ApoE)-/- mice reduced Western diet-induced plaque formation. Furthermore, thrombin induced Pyk2, Gab1, PKC?, and ATF2 phosphorylation, CD36 expression, and foam cell formation in peritoneal macrophages of ApoE-/- mice. In contrast, thrombin only stimulated Pyk2 and Gab1 but not ATF2 phosphorylation or its target gene CD36 expression in the peritoneal macrophages of ApoE-/-:PKC?-/- mice, and it had no effect on foam cell formation. In addition, the aortic root cross-sections of Western diet-fed ApoE-/- mice showed increased Pyk2, Gab1, PKC?, and ATF2 phosphorylation and CD36 expression as compared with ApoE-/-:PKC?-/- mice. Furthermore, although the monocytes from peripheral blood and the aorta of Western diet-fed ApoE-/- mice were found to contain more of Ly6Chi cells than Ly6Clo cells, the monocytes from Western diet-fed ApoE-/-:PKC?-/- mice were found to contain more Ly6Clo cells than Ly6Chi cells. It is interesting to note that the Ly6Chi cells showed higher CD36 expression with enhanced capacity to form foam cells as compared with Ly6Clo cells. CONCLUSIONS:These findings reveal for the first time that thrombin-mediated Par1-G?12 signaling via targeting Pyk2-Gab1-PKC?-ATF2-dependent CD36 expression might be playing a crucial role in diet-induced atherogenesis.

SUBMITTER: Raghavan S

PROVIDER: S-EPMC6309268 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Protein Kinase Cθ Via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6C<sup>hi</sup> Cells Contributes to Atherosclerosis.

Raghavan Somasundaram S Singh Nikhlesh K NK Gali Sivaiah S Mani Arul M AM Rao Gadiparthi N GN

Circulation 20181101 21

<h4>Background</h4>Although the role of thrombin in atherothrombosis is well studied, its role in the pathogenesis of diet-induced atherosclerosis is not known.<h4>Methods</h4>Using a mouse model of diet-induced atherosclerosis and molecular biological approaches, here we have explored the role of thrombin and its G protein-coupled receptor signaling in diet-induced atherosclerosis.<h4>Results</h4>In exploring the role of G protein-coupled receptor signaling in atherogenesis, we found that throm ...[more]

PMID: 29991487

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Project description:BackgroundThe accumulation of lipid-laden macrophages, foam cells, within sub-endothelial intima is a key feature of early atherosclerosis. Siglec-E, a mouse orthologue of human Siglec-9, is a sialic acid binding lectin predominantly expressed on the surface of myeloid cells to transduce inhibitory signal via recruitment of SH2-domain containing protein tyrosine phosphatase SHP-1/2 upon binding to its sialoglycan ligands. Whether Siglec-E expression on macrophages impacts foam cell formation and atherosclerosis remains to be established.MethodsApoE-deficient (apoE-/-) and apoE/Siglec-E-double deficient (apoE-/-/Siglec-E-/-) mice were placed on high fat diet for 3 months and their lipid profiles and severities of atherosclerosis were assessed. Modified low-density lipoprotein (LDL) uptake and foam cell formation in wild type (WT) and Siglec-E-/-- peritoneal macrophages were examined in vitro. Potential Siglec-E-interacting proteins were identified by proximity labeling in conjunction with proteomic analysis and confirmed by coimmunoprecipitation experiment. Impacts of Siglec-E expression and cell surface sialic acid status on oxidized LDL uptake and signaling involved were examined by biochemical assays.ResultsHere we show that genetic deletion of Siglec-E accelerated atherosclerosis without affecting lipid profile in apoE-/- mice. Siglec-E deficiency promotes foam cell formation by enhancing acetylated and oxidized LDL uptake without affecting cholesterol efflux in macrophages in vitro. By performing proximity labeling and proteomic analysis, we identified scavenger receptor CD36 as a cell surface protein interacting with Siglec-E. Further experiments performed in HEK293T cells transiently overexpressing Siglec-E and CD36 and peritoneal macrophages demonstrated that depletion of cell surface sialic acids by treatment with sialyltransferase inhibitor or sialidase did not affect interaction between Siglec-E and CD36 but retarded Siglec-E-mediated inhibition on oxidized LDL uptake. Subsequent experiments revealed that oxidized LDL induced transient Siglec-E tyrosine phosphorylation and recruitment of SHP-1 phosphatase in macrophages. VAV, a downstream effector implicated in CD36-mediated oxidized LDL uptake, was shown to interact with SHP-1 following oxidized LDL treatment. Moreover, oxidized LDL-induced VAV phosphorylation was substantially lower in WT macrophages comparing to Siglec-E-/- counterparts.ConclusionsThese data support the protective role of Siglec-E in atherosclerosis. Mechanistically, Siglec-E interacts with CD36 to suppress downstream VAV signaling involved in modified LDL uptake.

Project description:ObjectiveBy binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe-/- mice and IgE-deficient Ige-/- mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe-/-Ige-/- mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency.ConclusionsIgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.

Dataset Information

Protein Kinase C? Via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6Chi Cells Contributes to Atherosclerosis.

Publications

Protein Kinase Cθ Via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6C<sup>hi</sup> Cells Contributes to Atherosclerosis.

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