Macrophage paraoxonase 2 (PON2) expression is upregulated by unesterified cholesterol through activation of the phosphatidylinositol 3-kinase (PI3K) pathway

2007 ◽  
Vol 388 (12) ◽  
pp. 1353-1358 ◽  
Author(s):  
Maayan Shiner ◽  
Bianca Fuhrman ◽  
Michael Aviram
Keyword(s):  
Mrna Expression ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Progressive Increase ◽  
Pi3k Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Unesterified Cholesterol ◽  
Atherosclerotic Lesions ◽  
Acat Inhibitor ◽  
Phosphatidylinositol 3

Abstract Advanced atherosclerotic lesions are characterized by a progressive increase in the unesterified cholesterol (UC) content and a decrease in its cholesteryl ester (CE) content. In the present study, we examined mechanisms involved in the effect of UC and CE on the expression of paraoxonase 2 (PON2) in macrophages. J774A.1 macrophages were enriched with CE or UC by incubation for 14–48 h with 50 μg acetylated low-density lipoprotein in the absence or presence of the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor 58035 (50 μg/ml), respectively. Macrophage PON2 mRNA expression, protein abundance and activity were increased only in the UC-enriched cells. In UC-enriched cells, inhibition of phosphatidylinositol 3-kinase (PI3K; using wortmannin or LY294002) attenuated the increase in PON2 mRNA expression by 50%, compared to untreated cells. In addition, we evidenced an increased phosphorylation of Akt in UC-enriched cells. Thus, we conclude from our data that macrophage PON2 expression is upregulated in UC-enriched macrophages through activation of the PI3K signal pathway.

scholarly journals The neurorepellent, Slit2, prevents macrophage lipid loading by inhibiting CD36-dependent binding and internalization of oxidized low-density lipoprotein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bushra Yusuf ◽  
Ilya Mukovozov ◽  
Sajedabanu Patel ◽  
Yi-Wei Huang ◽  
Guang Ying Liu ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Super Resolution ◽  
Low Density ◽  
Dependent Manner ◽  
Oxidized Low Density Lipoprotein ◽  
Cortical Actin ◽  
Cytoskeletal Remodeling ◽  
Atherosclerotic Lesions ◽  
Modified Lipoproteins

AbstractAtherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions. The effects of Slit2 on oxLDL uptake by macrophages have not been explored. We report here that Slit2 inhibits uptake of oxLDL by human and murine macrophages, and the resulting formation of foam cells, in a Rac1-dependent and CD36-dependent manner. Exposure of macrophages to Slit2 prevented binding of oxLDL to the surface of cells. Using super-resolution microscopy, we observed that exposure of macrophages to Slit2 induced profound cytoskeletal remodeling with formation of a thick ring of cortical actin within which clusters of CD36 could not aggregate, thereby attenuating binding of oxLDL to the surface of cells. By inhibiting recruitment of monocytes into early atherosclerotic lesions, and the subsequent binding and internalization of oxLDL by macrophages, Slit2 could represent a potent new tool to combat individual steps that collectively result in progression of atherosclerosis.

scholarly journals Role of Phosphatidylinositol-3-Kinase Pathway in Head and Neck Squamous Cell Carcinoma

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Li Du ◽  
Jingping Shen ◽  
Andrew Weems ◽  
Shi-Long Lu
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Pi3k Pathway ◽  
Neck Squamous Cell Carcinoma ◽  
Phosphatidylinositol 3 Kinase ◽  
Molecular Alterations ◽  
Future Direction ◽  
Phosphatidylinositol 3

Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most frequently observed molecular alterations in many human malignancies, including head and neck squamous cell carcinoma (HNSCC). A growing body of evidence demonstrates the prime importance of the PI3K pathway at each stage of tumorigenesis, that is, tumor initiation, progression, recurrence, and metastasis. Expectedly, targeting the PI3K pathway yields some promising results in both preclinical studies and clinical trials for certain cancer patients. However, there are still many questions that need to be answered, given the complexity of this pathway and the existence of its multiple feedback loops and interactions with other signaling pathways. In this paper, we will summarize recent advances in the understanding of the PI3K pathway role in human malignancies, with an emphasis on HNSCC, and discuss the clinical applications and future direction of this field.

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