Review Article| Volume 348, ISSUE 2, P168-175, August 2014

Role of Interferon Alpha in Endothelial Dysfunction: Insights Into Endothelial Nitric Oxide Synthase–Related Mechanisms

  • Joy N. Jones Buie
    Correspondence: Joy N. Jones Buie, BS, Division of Rheumatology and Immunology, Department of Microbiology and Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, Clinical Sciences Building Suite 816, Charleston, SC 29425.
    From the Division of Rheumatology and Immunology in the Department of Medicine, Medical University of South Carolina; and Division of Rheumatology and Immunology, Department of Microbiology and Immunology, Medical Research Service of the Ralph H. Johnson VAMC, The Medical University of South Carolina, Charleston, South Carolina.
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  • Jim C. Oates
    From the Division of Rheumatology and Immunology in the Department of Medicine, Medical University of South Carolina; and Division of Rheumatology and Immunology, Department of Microbiology and Immunology, Medical Research Service of the Ralph H. Johnson VAMC, The Medical University of South Carolina, Charleston, South Carolina.
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      Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the production of autoantibodies against nuclear antigens such as double-stranded DNA. Lupus predominantly affects women (ratio, 9:1). Moreover, premenopausal women with SLE are 50 times more likely to have a myocardial infarction. Although specific risk factors for advanced cardiovascular complications have not been identified in this patient population, endothelial dysfunction is highly prevalent. Recent studies show that the type I interferon signature gene expression coincides with impaired brachial artery flow-mediated dilation and diminished endothelial progenitor cell circulation, both markers of impaired endothelial function. Although many factors promote the development of vascular endothelial dysfunction, all pathways converge on the diminished activity of endothelial nitric oxide synthase (eNOS) and loss of nitric oxide (NO) bioavailability. Studies examining the effects of type I interferons on eNOS and NO in SLE are missing. This literature review examines the current literature regarding the role of type I interferons in cardiovascular disease and its known effects on regulators of eNOS and NO bioavailability that are important for proper endothelial cell function.

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        • Berliner J.A.
        • Navab M.
        • Fogelman A.M.
        • et al.
        Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics.
        Circulation. 1995; 91: 2488-2496
        • Cominacini L.
        • Pasini A.F.
        • Garbin U.
        • et al.
        Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species.
        J Biol Chem. 2000; 275: 12633-12638
        • Cines D.B.
        • Pollak E.S.
        • Buck C.A.
        • et al.
        Endothelial cells in physiology and in the pathophysiology of vascular disorders.
        Blood. 1998; 91: 3527-3561
        • Fleming I.
        Molecular mechanisms underlying the activation of eNOS.
        Pflugers Arch. 2010; 459: 793-806
        • Amissah-Arthur M.B.
        • Gordon C.
        GPs have key role in shared care of patients with SLE.
        Practitioner. 2009; 253 (12): 19-24
        • Urowitz M.B.
        • Bookman A.A.M.
        • Koehler B.E.
        • et al.
        The bimodal mortality pattern of systemic lupus erythematosus.
        Am J Med. 1976; 60: 221-225
        • Korkmaz C.
        • Cansu D.U.
        • Kasifoglu T.
        Myocardial infarction in young patients (< or =35 years of age) with systemic lupus erythematosus: a case report and clinical analysis of the literature.
        Lupus. 2007; 16: 289-297
        • Jude E.B.
        • Douglas J.T.
        • Anderson S.G.
        • et al.
        Circulating cellular adhesion molecules ICAM-1, VCAM-1, P- and E-selectin in the prediction of cardiovascular disease in diabetes mellitus.
        Eur J Intern Med. 2002; 13: 185-189
        • Deanfield J.
        • Donald A.
        • Ferri C.
        • et al.
        Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the orking group on endothelin and endothelial factors of the European Society of Hypertension.
        J Hypertens. 2005; 23: 7-17
        • El-Magadmi M.
        • Bodill H.
        • Ahmad Y.
        • et al.
        Systemic lupus erythematosus: an independent risk factor for endothelial dysfunction in women.
        Circulation. 2004; 110: 399-404
        • Valdivielso P.
        • Gomez-Doblas J.J.
        • Macias M.
        • et al.
        Lupus-associated endothelial dysfunction, disease activity and arteriosclerosis.
        Clin Exp Rheumatol. 2008; 26: 827-833
        • Lee S.K.
        • Kim J.H.
        • Yang W.S.
        • et al.
        Exogenous nitric oxide inhibits VCAM-1 expression in human peritoneal mesothelial cells. Role of cyclic GMP and NF-kappaB.
        Nephron. 2002; 90: 447-454
        • Berendji-Grun D.
        • Kolb-Bachofen V.
        • Kroncke K.D.
        Nitric oxide inhibits endothelial IL-1[beta]-induced ICAM-1 gene expression at the transcriptional level decreasing Sp1 and AP-1 activity.
        Mol Med. 2001; 7: 748-754
        • Padmaja S.
        • Huie R.E.
        The reaction of nitric oxide with organic peroxyl radicals.
        Biochem Biophys Res Commun. 1993; 195: 539-544
        • Roberts W.
        • Michno A.
        • Aburima A.
        • et al.
        Nitric oxide inhibits von Willebrand factor-mediated platelet adhesion and spreading through regulation of integrin alpha(IIb)beta(3) and myosin light chain.
        J Thromb Haemost. 2009; 7: 2106-2115
        • Takeuchi K.
        • Watanabe H.
        • Tran Q.K.
        • et al.
        Nitric oxide: inhibitory effects on endothelial cell calcium signaling, prostaglandin I2 production and nitric oxide synthase expression.
        Cardiovasc Res. 2004; 62: 194-201
        • Zervou M.I.
        • Vazgiourakis V.M.
        • Yilmaz N.
        • et al.
        TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey.
        Hum Immunol. 2011; 72: 1210-1213
        • Tesauro M.
        • Thompson W.C.
        • Rogliani P.
        • et al.
        Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298.
        Proc Natl Acad Sci U S A. 2000; 97: 2832-2835
        • Miyamoto Y.
        • Saito Y.
        • Nakayama M.
        • et al.
        Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T–> mutation associated with coronary spastic angina.
        Hum Mol Genet. 2000; 9: 2629-2637
        • Anderson H.D.
        • Rahmutula D.
        • Gardner D.G.
        Tumor necrosis factor-alpha inhibits endothelial nitric-oxide synthase gene promoter activity in bovine aortic endothelial cells.
        The J Biol Chem. 2004; 279: 963-969
        • Nguyen H.
        • Chiasson V.L.
        • Chatterjee P.
        • et al.
        Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension.
        Cardiovasc Res. 2013; 97: 696-704
        • Chrobak I.
        • Lenna S.
        • Stawski L.
        • et al.
        Interferon-gamma promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) beta2.
        J Cell Physiol. 2013; 228: 1774-1783
        • Chen C.
        • Chai H.
        • Wang X.
        • et al.
        Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells.
        Blood. 2008; 112: 3205-3216
        • Venugopal S.K.
        • Devaraj S.
        • Yuhanna I.
        • et al.
        Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells.
        Circulation. 2002; 106: 1439-1441
        • Stauss H.M.
        • Godecke A.
        • Mrowka R.
        • et al.
        Enhanced blood pressure variability in eNOS knockout mice.
        Hypertension. 1999; 33: 1359-1363
        • Feng Q.
        • Song W.
        • Lu X.
        • et al.
        Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase.
        Circulation. 2002; 106: 873-879
        • Lee T.C.
        • Zhao Y.D.
        • Courtman D.W.
        • et al.
        Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase.
        Circulation. 2000; 101: 2345-2348
        • Lee P.C.
        • Salyapongse A.N.
        • Bragdon G.A.
        • et al.
        Impaired wound healing and angiogenesis in eNOS-deficient mice.
        Am J Physiol. 1999; 277: H1600-H1608
        • Pointer M.A.
        • Daumerie G.
        • Bridges L.
        • et al.
        Physiological stress increases renal injury in eNOS-knockout mice.
        Hypertens Res. 2012; 35: 318-324
        • Li Q.
        • Verma A.
        • Han P.Y.
        • et al.
        Diabetic eNOS-knockout mice develop accelerated retinopathy.
        Invest Ophthalmol Vis Sci. 2010; 51: 5240-5246
        • Mohan S.
        • Reddick R.L.
        • Musi N.
        • et al.
        Diabetic eNOS knockout mice develop distinct macro- and microvascular complications.
        Lab Invest. 2008; 88: 515-528
        • Duplain H.
        • Burcelin R.
        • Sartori C.
        • et al.
        Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase.
        Circulation. 2001; 104: 342-345
        • Knowles J.W.
        • Reddick R.L.
        • Jennette J.C.
        • et al.
        Enhanced atherosclerosis and kidney dysfunction in eNOS(-/-)Apoe(-/-) mice are ameliorated by enalapril treatment.
        J Clin Invest. 2000; 105: 451-458
        • Gilkeson G.S.
        • Mashmoushi A.K.
        • Ruiz P.
        • et al.
        Endothelial nitric oxide synthase reduces crescentic and necrotic glomerular lesions, reactive oxygen production, and MCP1 production in murine lupus nephritis.
        PLoS One. 2013; 8e64650
        • Al Gadban M.M.
        • German J.
        • Truman J.P.
        • et al.
        Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus.
        Cell Immunol. 2012; 276: 42-51
        • Somers E.C.
        • Zhao W.
        • Lewis E.E.
        • et al.
        Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients.
        PLoS One. 2012; 7e37000
        • Thacker S.G.
        • Zhao W.
        • Smith C.K.
        • et al.
        Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis.
        Arthritis Rheum. 2012; 64: 2975-2985
        • Lee P.Y.
        • Li Y.
        • Richards H.B.
        • et al.
        Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus.
        Arthritis Rheum. 2007; 56: 3759-3769
        • Ronnblom L.
        • Alm G.V.
        A pivotal role for the natural interferon alpha-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus.
        J Exp Med. 2001; 194: F59-F63
        • Ronnblom L.E.
        • Alm G.V.
        • Oberg K.E.
        Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour.
        J Intern Med. 1990; 227: 207-210
        • Levy Z.
        • Rachmani R.
        • Trestman S.
        • et al.
        Low-dose interferon-alpha accelerates atherosclerosis in an LDL receptor-deficient mouse model.
        Eur J Intern Med. 2003; 14: 479-483
        • Yao H.
        • Cao C.M.
        • Jin H.F.
        • et al.
        Treatment of interferon-alpha in reducing the endothelium-dependent relaxation of rat thoracic aorta.
        Zhejiang Da Xue Xue Bao Yi Xue Ban. 2003; 32: 202-206
        • Werner N.
        • Wassmann S.
        • Ahlers P.
        • et al.
        Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease.
        Basic Res Cardiol. 2007; 102: 565-571
        • Aicher A.
        • Heeschen C.
        • Mildner-Rihm C.
        • et al.
        Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells.
        Nat Med. 2003; 9: 1370-1376
        • Iwakura A.
        • Luedemann C.
        • Shastry S.
        • et al.
        Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury.
        Circulation. 2003; 108: 3115-3121
        • Laufs U.
        • Urhausen A.
        • Werner N.
        • et al.
        Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects.
        Eur J Cardiovasc Prev Rehabil. 2005; 12: 407-414
        • George A.L.
        • Bangalore-Prakash P.
        • Rajoria S.
        • et al.
        Endothelial progenitor cell biology in disease and tissue regeneration.
        J Hematol Oncol. 2011; 4: 24
        • Denny M.F.
        • Thacker S.
        • Mehta H.
        • et al.
        Interferon-alpha promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis.
        Blood. 2007; 110: 2907-2915
        • Teragawa H.
        • Hondo T.
        • Amano H.
        • et al.
        Cardiogenic shock following recombinant alpha-2b interferon therapy for chronic hepatitis C. A case report.
        Jpn Heart J. 1996; 37: 137-142
        • Lenci I.
        • Piccolo P.
        • Francioso S.
        • et al.
        Recurrent myocardial ischaemia during combination antiviral therapy in a patient with chronic hepatitis C and normal aminotransferase levels.
        Dig Liver Dis. 2008; 40: 785-790
        • Cauli C.
        • Serra G.
        • Chessa L.
        • et al.
        Severe autoimmune hemolytic anemia in a patient with chronic hepatitis C during treatment with peginterferon alfa-2a and ribavirin.
        Haematologica. 2006; 91: ECR26
        • Sasaki M.
        • Sata M.
        • Suzuki H.
        • et al.
        A case of chronic hepatitis C with sinus bradycardia during IFN therapy.
        Kurume Med J. 1998; 45: 161-163
        • Kouno H.
        • Aimitsu S.
        • Ikemoto Y.
        • et al.
        Cardiovascular complications of interferon therapy in chronic hepatitis C.
        Nihon Rinsho. 1994; 52: 1914-1918
        • Takase B.
        • Uehata A.
        • Fujioka T.
        • et al.
        Endothelial dysfunction and decreased exercise tolerance in interferon-alpha therapy in chronic hepatitis C: relation between exercise hyperemia and endothelial function.
        Clin Cardiol. 2001; 24: 286-290
        • Takase B.
        • Hamabe A.
        • Uehata A.
        • et al.
        Recombinant interferon alpha treatment decreases heart rate variability indices and impairs exercise tolerance in patients with chronic hepatitis.
        Biomed Pharmacother. 2005; 1: S163-S168
        • Panasiuk A.
        • Prokopowicz D.
        • Panasiuk B.
        Monocyte chemotactic protein-1 and soluble adhesion molecules as possible prognostic markers of the efficacy of antiviral treatment in chronic hepatitis C.
        World J Gastroenterol. 2004; 10: 3639-3642
        • Erol M.K.
        • Erol S.
        • Koruk M.
        • et al.
        Effects of interferon-alpha therapy on cardiac function in patients with chronic hepatitis B infection.
        Heart Vessels. 2004; 19: 263-266
        • Zhu Y.
        • Tibensky I.
        • Schmidt J.
        • et al.
        Interferon-alpha in combination with chemotherapy has potent antiangiogenic properties in an orthotopic mouse model for pancreatic adenocarcinoma.
        J Immunother. 2008; 31: 28-33
        • Radaeva S.
        • Jaruga B.
        • Hong F.
        • et al.
        Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes.
        Gastroenterology. 2002; 122: 1020-1034
        • Kumar S.
        • Sun X.
        • Wedgwood S.
        • et al.
        Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity.
        Am J Physiol Lung Cell Mol Physiol. 2008; 295: L370-L377
        • Adam L.
        • Black P.C.
        • Kassouf W.
        • et al.
        Adenoviral mediated interferon-alpha 2b gene therapy suppresses the pro-angiogenic effect of vascular endothelial growth factor in superficial bladder cancer.
        J Urol. 2007; 177: 1900-1906
        • Schwartz R.
        • Osborne-Lawrence S.
        • Hahner L.
        • et al.
        C-reactive protein downregulates endothelial NO synthase and attenuates reendothelialization in vivo in mice.
        Circ Res. 2007; 100: 1452-1459
        • Yang X.
        • Nath A.
        • Opperman M.J.
        • et al.
        The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells.
        Mol Biol Cell. 2010; 21: 3449-3458
        • Chu W.M.
        • Ostertag D.
        • Li Z.W.
        • et al.
        JNK2 and IKKbeta are required for activating the innate response to viral infection.
        Immunity. 1999; 11: 721-731
        • Goh K.C.
        • deVeer M.J.
        • Williams B.R.
        The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin.
        EMBO J. 2000; 19: 4292-4297
        • Salven P.
        • Anttonen K.
        • Repo H.
        • et al.
        Endotoxins induce and interferon alpha suppresses vascular endothelial growth factor (VEGF) production in human peripheral blood mononuclear cells.
        FASEB J. 2001; 15: 1318-1320
        • Wada H.
        • Nagano H.
        • Yamamoto H.
        • et al.
        Combination of interferon-alpha and 5-fluorouracil inhibits endothelial cell growth directly and by regulation of angiogenic factors released by tumor cells.
        BMC Cancer. 2009; 9: 361
        • Tsutsui M.
        • Milstien S.
        • Katusic Z.S.
        Effect of tetrahydrobiopterin on endothelial function in canine middle cerebral arteries.
        Circ Res. 1996; 79: 336-342
        • Katusic Z.S.
        • d'Uscio L.V.
        Tetrahydrobiopterin: mediator of endothelial protection.
        Arterioscler Thromb Vasc Biol. 2004; 24: 397-398
        • Forstermann U.
        • Closs E.I.
        • Pollock J.S.
        • et al.
        Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions.
        Hypertension. 1994; 23: 1121-1131
        • Harrison D.G.
        Cellular and molecular mechanisms of endothelial cell dysfunction.
        J Clin Invest. 1997; 100: 2153-2157
        • Kitagami T.
        • Yamada K.
        • Miura H.
        • et al.
        Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood-brain barrier.
        Brain Res. 2003; 978: 104-114
        • Felger J.C.
        • Li L.
        • Marvar P.J.
        • et al.
        Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations.
        Brain Behav Immun. 2013; 31: 153-160
        • Cosentino F.
        • Patton S.
        • d'Uscio L.V.
        • et al.
        Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats.
        J Clin Invest. 1998; 101: 1530-1537
        • Schildknecht S.
        • van der Loo B.
        • Weber K.
        • et al.
        Endogenous peroxynitrite modulates PGHS-1-dependent thromboxane A2 formation and aggregation in human platelets.
        Free Radic Biol Med. 2008; 45: 512-520
        • Casanello P.
        • Krause B.
        • Torres E.
        • et al.
        Reduced l-arginine transport and nitric oxide synthesis in human umbilical vein endothelial cells from intrauterine growth restriction pregnancies is not further altered by hypoxia.
        Placenta. 2009; 30: 625-633
        • Shin W.S.
        • Berkowitz D.E.
        • Ryoo S.W.
        Increased arginase II activity contributes to endothelial dysfunction through endothelial nitric oxide synthase uncoupling in aged mice.
        Exp Mol Med. 2012; 44: 594-602
        • Kim J.H.
        • Bugaj L.J.
        • Oh Y.J.
        • et al.
        Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats.
        J Appl Physiol (1985). 2009; 107: 1249-1257
        • Fekkes D.
        • Bannink M.
        • Kruit W.H.
        • et al.
        Influence of pegylated interferon-alpha therapy on plasma levels of citrulline and arginine in melanoma patients.
        Amino Acids. 2007; 32: 121-126
        • Lu D.Y.
        • Leung Y.M.
        • Su K.P.
        Interferon-alpha induces nitric oxide synthase expression and haem oxygenase-1 down-regulation in microglia: implications of cellular mechanism of IFN-alpha-induced depression.
        Int J Neuropsychopharmacol. 2013; 16: 433-444
        • Arnal J.F.
        • Tack I.
        • Besombes J.P.
        • et al.
        Nitric oxide and superoxide anion production during endothelial cell proliferation.
        Am J Physiol. 1996; 271: C1521-C1526
        • Sukumar P.
        • Viswambharan H.
        • Imrie H.
        • et al.
        Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction.
        Diabetes. 2013; 62: 2130-2134
        • Guzik T.J.
        • Sadowski J.
        • Kapelak B.
        • et al.
        Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1614-1620
        • Kou B.
        • Ni J.
        • Vatish M.
        • et al.
        Xanthine oxidase interaction with vascular endothelial growth factor in human endothelial cell angiogenesis.
        Microcirculation. 2008; 15: 251-267
        • Alp N.J.
        • McAteer M.A.
        • Khoo J.
        • et al.
        Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice.
        Arteriosclerosis Thromb Vasc Biol. 2004; 24: 445-450
        • Singh U.
        • Devaraj S.
        • Vasquez-Vivar J.
        • et al.
        C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling.
        J Mol Cell Cardiol. 2007; 43: 780-791
        • Munzel T.
        • Daiber A.
        • Ullrich V.
        • et al.
        Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase.
        Arteriosclerosis Thromb Vasc Biol. 2005; 25: 1551-1557
        • Nistala R.
        • Whaley-Connell A.
        • Sowers J.R.
        Redox control of renal function and hypertension.
        Antioxid Redox Signal. 2008; 10: 2047-2089
        • Nishiwaki H.
        • Ogura Y.
        • Miyamoto K.
        • et al.
        Prednisolone, platelet-activating factor receptor antagonist, or superoxide dismutase reduced leukocyte entrapment induced by interferon alpha in retinal microcirculation.
        Invest Ophthalmol Vis Sci. 1997; 38: 811-816