Signal Transducer and Activator of Transcription 1 Is Required for Optimal Foam Cell Formation and Atherosclerotic Lesion Development
- 12 June 2007
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Cell Metabolism
- Vol. 115 (23), 2939-2947
- https://doi.org/10.1161/circulationaha.107.696922
Abstract
Background— Signal transducer and activator of transcription 1 (Stat1) potently regulates gene expression after stimulation by certain cytokines involved in tumorigenesis and host defenses. The present study investigated a novel role for Stat1 in foam cell formation and atherosclerosis. Methods and Results— Inhibition of Stat1 activity by a Stat1-specific DNA “decoy” oligomer transfected into differentiated human THP-1 cells, and deficiency of stat1 in mouse macrophages significantly inhibited foam cell formation assessed by lipid staining and cholesteryl ester accumulation compared with control cells. The mechanism of Stat1 regulation of foam cell formation was uniquely dependent on the scavenger receptor CD36. Blunted Stat1 activity and stat1 deficiency significantly decreased expression of CD36 but not of scavenger receptor-A compared with controls, as assessed by immunoblotting and flow cytometry. Deficiency of CD36 but not scavenger receptor-A in mouse macrophages removed any dependency of foam cell formation on Stat1. In an intraperitoneal model of foam cell formation in which foam cells form in vivo independently of the model ligands used in vitro, stat1 deficiency significantly inhibited foam cell formation and CD36 expression. Transplantation of bone marrow from apolipoprotein e − / − × stat1 − / − mice into lethally irradiated, atherosclerosis-susceptible apolipoprotein e −/− recipients significantly reduced both en face aortic lesion coverage and aortic root lesions compared with recipients of bone marrow from genetically matched apolipoprotein e −/− mice. Conclusions— Stat1 regulates CD36 expression and foam cell formation in macrophages in vitro; the Stat1 regulation of foam cell formation requires CD36. The regulation of CD36 expression by Stat1 may be important in other pathophysiological CD36-dependent events. Stat1 deficiency reduces atherosclerosis in an apolipoprotein e −/− atherosclerosis-susceptible bone marrow transplantation model.Keywords
This publication has 41 references indexed in Scilit:
- Effects of Obesity on Lipid-Lowering, Anti-Inflammatory, and Antiatherosclerotic Benefits of Atorvastatin or Pravastatin in Patients With Coronary Artery Disease (from the REVERSAL Study)The American Journal of Cardiology, 2006
- Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasisJournal of Lipid Research, 2006
- Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic miceJCI Insight, 2005
- Stem Cell Transplantation Reveals That Absence of Macrophage CD36 Is Protective Against AtherosclerosisArteriosclerosis, Thrombosis, and Vascular Biology, 2004
- Differential Effects of Green Tea–Derived Catechin on Developing Versus Established Atherosclerosis in Apolipoprotein E–Null MiceCirculation, 2004
- CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolismJCI Insight, 2001
- How Stat1 mediates constitutive gene expression: a complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 geneThe EMBO Journal, 2000
- Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen speciesJCI Insight, 2000
- Effects of Interferon-α, β, and γ on the Function of Differentiated Leukemic HL-60 Cells Induced by 1,25-Dihydroxyvitamin D3Journal of Interferon & Cytokine Research, 1996
- Inactivation of lysosomal proteases by oxidized low density lipoprotein is partially responsible for its poor degradation by mouse peritoneal macrophages.JCI Insight, 1994