Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis.

OBJECTIVE Patients with systemic lupus erythematosus (SLE) have a notable increase in atherothrombotic cardiovascular disease (CVD) which is not explained by the Framingham risk equation. In vitro studies indicate that type I interferons (IFNs) may play prominent roles in increased CV risk in SLE. However, the in vivo relevance of these findings, with regard to the development of CVD, has not been characterized. This study was undertaken to examine the role of type I IFNs in endothelial dysfunction, aberrant vascular repair, and atherothrombosis in murine models of lupus and atherosclerosis. METHODS Lupus-prone New Zealand mixed 2328 (NZM) mice and atherosclerosis-prone apolipoprotein E- knockout (apoE(-/-) ) mice were compared to mice lacking type I IFN receptor (INZM and apoE(-/-) IFNAR(-/-) mice, respectively) with regard to endothelial vasodilatory function, endothelial progenitor cell (EPC) function, in vivo neoangiogenesis, plaque development, and occlusive thrombosis. Similar experiments were performed using NZM and apoE(-/-) mice exposed to an IFNα-containing or empty adenovirus. RESULTS Loss of type I IFN receptor signaling improved endothelium-dependent vasorelaxation, lipoprotein parameters, EPC numbers and function, and neoangiogenesis in lupus-prone mice, independent of disease activity or sex. Further, acute exposure to IFNα impaired endothelial vasorelaxation and EPC function in lupus-prone and non-lupus-prone mice. Decreased atherosclerosis severity and arterial inflammatory infiltrates and increased neoangiogenesis were observed in apoE(-/-) IFNAR(-/-) mice, compared to apoE(-/-) mice, while NZM and apoE(-/-) mice exposed to IFNα developed accelerated thrombosis and platelet activation. CONCLUSION These results support the hypothesis that type I IFNs play key roles in the development of premature CVD in SLE and, potentially, in the general population, through pleiotropic deleterious effects on the vasculature.

[1]  B. Sundaram,et al.  Type I Interferons Are Associated with Subclinical Markers of Cardiovascular Disease in a Cohort of Systemic Lupus Erythematosus Patients , 2012, PloS one.

[2]  C. Bao,et al.  Interferon-α priming promotes lipid uptake and macrophage-derived foam cell formation: a novel link between interferon-α and atherosclerosis in lupus. , 2011, Arthritis and rheumatism.

[3]  S. Pennathur,et al.  Quantitative analysis of amino Acid oxidation markers by tandem mass spectrometry. , 2011, Methods in enzymology.

[4]  M. Hayden,et al.  The dynamics of macrophage infiltration into the arterial wall during atherosclerotic lesion development in low-density lipoprotein receptor knockout mice. , 2011, The American journal of pathology.

[5]  J. Małyszko.  Mechanism of endothelial dysfunction in chronic kidney disease. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[6]  M. Rastaldi,et al.  The Detrimental Effects of IFN-α on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction , 2010, The Journal of Immunology.

[7]  E. Falk,et al.  Atherosclerotic lesions in mouse and man: is it the same disease? , 2010, Current opinion in lipidology.

[8]  L. Truedsson,et al.  Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. , 2010, Blood.

[9]  I. van der Made,et al.  Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. , 2010, Cell metabolism.

[10]  A. Koch,et al.  Junctional Adhesion Molecule-C Is a Soluble Mediator of Angiogenesis , 2010, The Journal of Immunology.

[11]  M. Crow.  Interferon-alpha: a therapeutic target in systemic lupus erythematosus. , 2010, Rheumatic diseases clinics of North America.

[12]  D. Fliser,et al.  Endothelial progenitor cells in chronic kidney disease. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[13]  James L. Park,et al.  Lupus-prone New Zealand Black/New Zealand White F1 mice display endothelial dysfunction and abnormal phenotype and function of endothelial progenitor cells , 2010, Lupus.

[14]  P. Toth.  Dysfunctional Proinflammatory High-Density Lipoproteins Confer Increased Risk of Atherosclerosis in Women With Systemic Lupus Erythematosus , 2010 .

[15]  James L. Park,et al.  The Peroxisome Proliferator-Activated Receptor γ Agonist Pioglitazone Improves Cardiometabolic Risk and Renal Inflammation in Murine Lupus1 , 2009, The Journal of Immunology.

[16]  T. Suda,et al.  Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion , 2009, Nature Medicine.

[17]  L. Cámera,et al.  Recent Respiratory Infection Predicts Atherothrombotic Stroke: Case–Control Study in a Buenos Aires Healthcare System , 2009, Stroke.

[18]  M. Madaio,et al.  Interferon-alpha treatment of female (NZW x BXSB)F(1) mice mimics some but not all features associated with the Yaa mutation. , 2009, Arthritis and rheumatism.

[19]  Yi Li,et al.  Type I interferon modulates monocyte recruitment and maturation in chronic inflammation. , 2009, The American journal of pathology.

[20]  M. Madaio,et al.  Interferon-Treatment of Female ( NZW BXSB ) F 1 Mice Mimics Some but Not All Features Associated With the Yaa Mutation , 2009 .

[21]  E. Borden,et al.  Identification of interferon-beta-stimulated genes that inhibit angiogenesis in vitro. , 2008, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[22]  M. Monestier,et al.  Accelerated atherosclerosis in ApoE deficient lupus mouse models. , 2008, Clinical immunology.

[23]  U. R. Chowdhury,et al.  Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization. , 2008, The Journal of clinical investigation.

[24]  Kindra M Kelly-Scumpia,et al.  Deficiency of the type I interferon receptor protects mice from experimental lupus. , 2007, Arthritis and rheumatism.

[25]  M. Segal,et al.  Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus. , 2007, Arthritis and rheumatism.

[26]  M. Shin,et al.  Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-&agr; and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque , 2007, Circulation.

[27]  W. Mccune,et al.  Interferon-α promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis , 2007 .

[28]  E. Gautier,et al.  Enhanced Immune System Activation and Arterial Inflammation Accelerates Atherosclerosis in Lupus-Prone Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[29]  A. Arbab,et al.  The role of vascular cell adhesion molecule 1/ very late activation antigen 4 in endothelial progenitor cell recruitment to rheumatoid arthritis synovium. , 2007, Arthritis and rheumatism.

[30]  W. Hsueh,et al.  Recipes for creating animal models of diabetic cardiovascular disease. , 2007, Circulation research.

[31]  A. La Cava,et al.  ApoE−/−Fas−/− C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis, and osteopenia Published, JLR Papers in Press, January 26, 2007. , 2007, Journal of Lipid Research.

[32]  I. Young,et al.  High density lipoprotein subfractions: isolation, composition, and their duplicitous role in oxidation Published, JLR Papers in Press, October 25, 2006. , 2007, Journal of Lipid Research.

[33]  P. Goldschmidt-Clermont,et al.  Aging in the Atherosclerosis Milieu May Accelerate the Consumption of Bone Marrow Endothelial Progenitor Cells , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[34]  V. Pascual,et al.  Type I interferon in systemic lupus erythematosus and other autoimmune diseases. , 2006, Immunity.

[35]  K. Kalunian,et al.  Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[36]  N. Olsen,et al.  Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. R. Berger,et al.  Risk of Myocardial Infarction and Stroke After Acute Infection or Vaccination , 2006 .

[38]  P. Galle,et al.  Interferon- (cid:1) : A Therapeutic for Autoimmune Lupus in MRL- Fas lpr Mice , 2022 .

[39]  P. Bodary,et al.  Recombinant Leptin Promotes Atherosclerosis and Thrombosis in Apolipoprotein E—Deficient Mice , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[40]  A. Chait,et al.  Human Atherosclerotic Intima and Blood of Patients with Established Coronary Artery Disease Contain High Density Lipoprotein Damaged by Reactive Nitrogen Species* , 2004, Journal of Biological Chemistry.

[41]  Jonathan D. Hron,et al.  Type I IFN Protects Against Murine Lupus1 , 2004, The Journal of Immunology.

[42]  R. Brook,et al.  Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. , 2004, Blood.

[43]  K. Walsh,et al.  Impaired Clearance of Apoptotic Cells Promotes Synergy between Atherogenesis and Autoimmune Disease , 2004, The Journal of experimental medicine.

[44]  E. Coccia,et al.  Viral infection and Toll‐like receptor agonists induce a differential expression of type I and λ interferons in human plasmacytoid and monocyte‐derived dendritic cells , 2004, European journal of immunology.

[45]  J. Kaufman,et al.  IFN-α Sensitizes Human Umbilical Vein Endothelial Cells to Apoptosis Induced by Double-Stranded RNA1 , 2004, The Journal of Immunology.

[46]  G. Hughes,et al.  Morbidity and Mortality in Systemic Lupus Erythematosus During a 10-Year Period: A Comparison of Early and Late Manifestations in a Cohort of 1,000 Patients , 2003, Medicine.

[47]  O. Volpert,et al.  Migration Inhibitory Factor Mediates Angiogenesis via Mitogen-Activated Protein Kinase and Phosphatidylinositol Kinase , 2003, Circulation research.

[48]  Andreas Schober,et al.  Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E , 2003, Nature Medicine.

[49]  M. Abrahamowicz,et al.  Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. , 2001, Arthritis and rheumatism.

[50]  K. Tung,et al.  NZM2328: a new mouse model of systemic lupus erythematosus with unique genetic susceptibility loci. , 2001, Clinical immunology.

[51]  G. Sturfelt,et al.  Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies , 2000, Lupus.

[52]  E. Nabel,et al.  Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. , 2000, Blood.

[53]  R. D'Agostino,et al.  Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. , 1997, American journal of epidemiology.

[54]  P. Ganz,et al.  Systemic nature of endothelial dysfunction in atherosclerosis. , 1995, The American journal of cardiology.

[55]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[56]  R. Zinkernagel,et al.  Immune response in mice that lack the interferon-gamma receptor. , 1993, Science.