ApoE−/− PGC-1α−/− Mice Display Reduced IL-18 Levels and Do Not Develop Enhanced Atherosclerosis

Background Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model. Methodology/Principal Findings To investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE−/− PGC-1α−/− did not display more or larger atherosclerotic plaques than their ApoE−/− PGC-1α+/+ littermates. In line with the previously published phenotype of PGC-1α−/− mice, ApoE−/− PGC-1α−/− mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentitation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE−/− PGC-1α−/− mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE−/− PGC-1α−/− mice. Conclusions/Significance ApoE−/− PGC-1α−/− mice, similar as PGC-1α−/− mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis.

[1]  Min-Seon Kim,et al.  Peroxisome Proliferator-Activated Receptor-&ggr; Coactivator 1-&agr; Overexpression Prevents Endothelial Apoptosis by Increasing ATP/ADP Translocase Activity , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[2]  B. Becher,et al.  SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis , 2009, European heart journal.

[3]  T. Kita,et al.  Circulating soluble SR-PSOX/CXCL16 as a biomarker for acute coronary syndrome -comparison with high-sensitivity C-reactive protein. , 2009, Journal of atherosclerosis and thrombosis.

[4]  M. Reiser,et al.  Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis. , 2009, European journal of endocrinology.

[5]  F. Schick,et al.  RARRES2, encoding the novel adipokine chemerin, is a genetic determinant of disproportionate regional body fat distribution: a comparative magnetic resonance imaging study. , 2009, Metabolism: clinical and experimental.

[6]  Le-ming Fan,et al.  ASSOCIATION BETWEEN PPARGC1A GENE POLYMORPHISMS AND CORONARY ARTERY DISEASE IN A CHINESE POPULATION , 2008, Clinical and experimental pharmacology & physiology.

[7]  Peter Tontonoz,et al.  Fat and beyond: the diverse biology of PPARgamma. , 2008, Annual review of biochemistry.

[8]  D. Lawrence,et al.  Visceral Adipose Tissue Inflammation Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice , 2008, Circulation.

[9]  M. Halks-Miller,et al.  Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice , 2008, Gene Therapy.

[10]  A. Khera,et al.  The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart Study. , 2007, Journal of the American College of Cardiology.

[11]  Hyoung-Tae Kim,et al.  Effects of PGC-1α on TNF-α–Induced MCP-1 and VCAM-1 Expression and NF-κB Activation in Human Aortic Smooth Muscle and Endothelial Cells , 2006 .

[12]  A. Hamsten,et al.  Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6. , 2006, Atherosclerosis.

[13]  H. Suchanek,et al.  High serum interleukin-18 concentrations in patients with coronary artery disease and type 2 diabetes mellitus. , 2005, European cytokine network.

[14]  D. Vaughan.  PAI‐1 and atherothrombosis , 2005, Journal of thrombosis and haemostasis : JTH.

[15]  Ildikó Kriszbacher,et al.  Inflammation, atherosclerosis, and coronary artery disease. , 2005, New England Journal of Medicine.

[16]  Christoph Handschin,et al.  Metabolic control through the PGC-1 family of transcription coactivators. , 2005, Cell metabolism.

[17]  Xinghua Zhou,et al.  IL-18 Accelerates Atherosclerosis Accompanied by Elevation of IFN-&ggr; and CXCL16 Expression Independently of T Cells , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[18]  Jiandie D. Lin,et al.  Defects in Adaptive Energy Metabolism with CNS-Linked Hyperactivity in PGC-1α Null Mice , 2004, Cell.

[19]  Allan R Brasier,et al.  Liver gene expression associated with diet and lesion development in atherosclerosis-prone mice: induction of components of alternative complement pathway. , 2004, Physiological genomics.

[20]  T. Kita,et al.  Chemokines Generally Exhibit Scavenger Receptor Activity through Their Receptor-binding Domain* , 2004, Journal of Biological Chemistry.

[21]  S. Rose-John,et al.  The Transmembrane CXC-Chemokine Ligand 16 Is Induced by IFN-γ and TNF-α and Shed by the Activity of the Disintegrin-Like Metalloproteinase ADAM10 1 , 2004, The Journal of Immunology.

[22]  P. Dempsey,et al.  A Disintegrin and Metalloproteinase 10-Mediated Cleavage and Shedding Regulates the Cell Surface Expression of CXC Chemokine Ligand 16 , 2004, The Journal of Immunology.

[23]  T. Kita,et al.  Cell surface‐anchored SR‐PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6‐expressing cells , 2004, Journal of leukocyte biology.

[24]  Marc Parmentier,et al.  Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids , 2003, The Journal of experimental medicine.

[25]  S. Akira,et al.  Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. , 2003, Cardiovascular research.

[26]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[27]  R. Evans,et al.  Peroxisome-Proliferator-Activated Receptor δ Activates Fat Metabolism to Prevent Obesity , 2003, Cell.

[28]  F. Krempler,et al.  Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 alpha. , 2003, The Biochemical journal.

[29]  P. Puigserver,et al.  Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. , 2003, Endocrine reviews.

[30]  T. Lakka,et al.  Abdominal obesity is associated with increased risk of acute coronary events in men. , 2002, European heart journal.

[31]  D. Kressler,et al.  The PGC-1-related Protein PERC Is a Selective Coactivator of Estrogen Receptor α* , 2002, The Journal of Biological Chemistry.

[32]  C. Glass,et al.  Conditional Disruption of the Peroxisome Proliferator-Activated Receptor γ Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux , 2002, Molecular and Cellular Biology.

[33]  A. Daugherty,et al.  Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E−/− Mice Through Release of Interferon-&ggr; , 2002, Circulation research.

[34]  A. Tedgui,et al.  Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Atherosclerotic Lesion Development and Stability , 2001, Circulation research.

[35]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[36]  F. Castellino,et al.  Attenuation of Neointima Formation Following Arterial Injury in PAI‐1 Deficient Mice , 2001, Annals of the New York Academy of Sciences.

[37]  Christopher K. Glass,et al.  Atherosclerosis The Road Ahead , 2001, Cell.

[38]  T. Kita,et al.  Molecular Cloning of a Novel Scavenger Receptor for Oxidized Low Density Lipoprotein, SR-PSOX, on Macrophages* , 2000, The Journal of Biological Chemistry.

[39]  Sharon Engel,et al.  A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo , 2000, Nature Immunology.

[40]  Andrew C. Li,et al.  Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice , 2000 .

[41]  Rick B. Vega,et al.  The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor α in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes , 2000, Molecular and Cellular Biology.

[42]  M. Daemen,et al.  Requirement for CD154 in the progression of atherosclerosis , 1999, Nature Medicine.

[43]  W. Wahli,et al.  Peroxisome proliferator-activated receptors: nuclear control of metabolism. , 1999, Endocrine reviews.

[44]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[45]  Robert V Farese,et al.  Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet. , 1995, The Journal of clinical investigation.

[46]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[47]  B. Spiegelman,et al.  Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. , 1992, The Journal of biological chemistry.

[48]  B. Spiegelman,et al.  Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. , 1987, Science.

[49]  B. Spiegelman,et al.  Severely impaired adipsin expression in genetic and acquired obesity. , 1987, Science.

[50]  B. Spiegelman,et al.  Adipsin, the adipocyte serine protease: gene structure and control of expression by tumor necrosis factor. , 1986, Nucleic acids research.

[51]  Hyoung-Tae Kim,et al.  Effects of PGC-1alpha on TNF-alpha-induced MCP-1 and VCAM-1 expression and NF-kappaB activation in human aortic smooth muscle and endothelial cells. , 2007, Antioxidants & redox signaling.

[52]  R. Evans,et al.  Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. , 2003, Cell.

[53]  Jerry Donovan,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. , 2003, Nature.

[54]  R. Evans,et al.  A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. , 2001, Molecular cell.

[55]  R. Evans,et al.  A PPARγ-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis , 2001 .

[56]  T. Willson,et al.  Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. , 2000, The Journal of clinical investigation.

[57]  Y. Li,et al.  Bmc Cardiovascular Disorders the Impact of Severity of Hypertension on Association of Pgc-1α Gene with Blood Pressure and Risk of Hypertension , 2022 .