Immune activation caused by vascular oxidation promotes fibrosis and hypertension.

Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN-γ. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-γ, IL-17A, and TNF-α. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.

[1]  D. Levy,et al.  Changes in Arterial Stiffness and Wave Reflection With Advancing Age in Healthy Men and Women: The Framingham Heart Study , 2004, Hypertension.

[2]  D. Harrison,et al.  Interleukin 17 Promotes Angiotensin II–Induced Hypertension and Vascular Dysfunction , 2010, Hypertension.

[3]  D. Heistad,et al.  Effects of local reduction in pressure on distensibility and composition of cerebral arterioles. , 1991, Circulation research.

[4]  G. Kojda,et al.  Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice. , 2005, American journal of physiology. Heart and circulatory physiology.

[5]  L. Topoleski,et al.  The effect of oxidation on the mechanical response and microstructure of porcine aortas. , 2014, Journal of biomedical materials research. Part A.

[6]  Chao-Yu Guo,et al.  Cross-Sectional Correlates of Increased Aortic Stiffness in the Community: The Framingham Heart Study , 2007, Circulation.

[7]  D. Levy,et al.  Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. , 2015, The Journal of clinical investigation.

[8]  F. Faraci,et al.  IL-6 Deficiency Protects Against Angiotensin II–Induced Endothelial Dysfunction and Hypertrophy , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[9]  R. Mecham,et al.  Methods in elastic tissue biology: elastin isolation and purification. , 2008, Methods.

[10]  D. Atar,et al.  Tumor Necrosis Factor-&agr; Antagonists Improve Aortic Stiffness in Patients With Inflammatory Arthropathies: A Controlled Study , 2010, Hypertension.

[11]  L. Sandberg,et al.  Mechanisms of lung injury in the copper-deficient hamster model of emphysema. , 1984, Chest.

[12]  D. Levy,et al.  Components of Hemodynamic Load and Cardiovascular Events: The Framingham Heart Study , 2015, Circulation.

[13]  D. Weiss,et al.  Inhibition and Genetic Ablation of the B7/CD28 T-Cell Costimulation Axis Prevents Experimental Hypertension , 2010, Circulation.

[14]  D. Harrison,et al.  Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction , 2007, The Journal of experimental medicine.

[15]  B. Starcher,et al.  A ninhydrin-based assay to quantitate the total protein content of tissue samples. , 2001, Analytical biochemistry.

[16]  E. Lapointe,et al.  Insights into rheumatoid arthritis derived from the Sa immune system , 2000, Arthritis research.

[17]  S. Laurent,et al.  Aortic Stiffness Is an Independent Predictor of Fatal Stroke in Essential Hypertension , 2003, Stroke.

[18]  F. Ginhoux,et al.  Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. , 2013, Immunity.

[19]  P. Galan,et al.  Effect of supplementation with antioxidants upon long-term risk of hypertension in the SU.VI.MAX study: association with plasma antioxidant levels , 2005, Journal of hypertension.

[20]  D. Harrison,et al.  Oligoclonal CD8+ T Cells Play a Critical Role in the Development of Hypertension , 2014, Hypertension.

[21]  M. Kals,et al.  Inflammation and oxidative stress are associated differently with endothelial function and arterial stiffness in healthy subjects and in patients with atherosclerosis , 2008, Scandinavian journal of clinical and laboratory investigation.

[22]  K. Hofman,et al.  High-throughput quantification of hydroxyproline for determination of collagen. , 2011, Analytical biochemistry.

[23]  E. Fleck,et al.  Aortic stiffness, impaired fasting glucose, and aging. , 2010, Hypertension.

[24]  D. Harrison,et al.  Inflammation and Mechanical Stretch Promote Aortic Stiffening in Hypertension Through Activation of p38 Mitogen-Activated Protein Kinase , 2013, Circulation research.

[25]  J. Fessel,et al.  Localization of isoketal adducts in vivo using a single-chain antibody. , 2004, Free radical biology & medicine.

[26]  Sang Min Park,et al.  Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials , 2013, BMJ.

[27]  J. Morrow,et al.  The relationship between dose of vitamin E and suppression of oxidative stress in humans. , 2007, Free radical biology & medicine.

[28]  J. Diehl,et al.  Hypoxic Reactive Oxygen Species Regulate the Integrated Stress Response and Cell Survival , 2008, Journal of Biological Chemistry.

[29]  A. J. Valente,et al.  Interleukin-17A stimulates cardiac fibroblast proliferation and migration via negative regulation of the dual-specificity phosphatase MKP-1/DUSP-1. , 2012, Cellular signalling.

[30]  P. Gisondi,et al.  Chronic Plaque Psoriasis Is Associated with Increased Arterial Stiffness , 2008, Dermatology.

[31]  O. Boutaud,et al.  Measurement of chronic oxidative and inflammatory stress by quantification of isoketal/levuglandin γ-ketoaldehyde protein adducts using liquid chromatography tandem mass spectrometry , 2007, Nature Protocols.

[32]  D. Harrison,et al.  DC isoketal-modified proteins activate T cells and promote hypertension. , 2014, The Journal of clinical investigation.

[33]  Daniel Levy,et al.  Aortic stiffness, blood pressure progression, and incident hypertension. , 2012, JAMA.

[34]  P. Chatterjee,et al.  Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. , 2013, Cardiovascular research.

[35]  Christian Gluud,et al.  Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. , 2007, JAMA.

[36]  H. Jacob,et al.  Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. , 2013, American journal of physiology. Regulatory, integrative and comparative physiology.

[37]  K. Amano,et al.  Tocilizumab Monotherapy Reduces Arterial Stiffness as Effectively as Etanercept or Adalimumab Monotherapy in Rheumatoid Arthritis: An Open-label Randomized Controlled Trial , 2011, The Journal of Rheumatology.

[38]  D. Harrison,et al.  Role of Vascular Extracellular Superoxide Dismutase in Hypertension , 2011, Hypertension.

[39]  L. Kuller,et al.  Vascular Stiffness in Women With Systemic Lupus Erythematosus , 2001, Hypertension.

[40]  N. Matsumi,et al.  Lysine pyrrolation is a naturally-occurring covalent modification involved in the production of DNA mimic proteins , 2014, Scientific Reports.

[41]  Ciriana Orabona,et al.  CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86 , 2004, Nature Immunology.

[42]  M. Kleinewietfeld,et al.  Interferon-&ggr; Signaling Inhibition Ameliorates Angiotensin II–Induced Cardiac Damage , 2012, Hypertension.

[43]  A. Whalen,et al.  Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Cynthia A. Reinhart-King,et al.  Arterial Stiffening Precedes Systolic Hypertension in Diet-Induced Obesity , 2013, Hypertension.

[45]  S. Hazen,et al.  Carbamylation-Dependent Activation of T Cells: A Novel Mechanism in the Pathogenesis of Autoimmune Arthritis , 2010, The Journal of Immunology.

[46]  Hiroaki Shimokawa,et al.  Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. , 2002, Biochemical and biophysical research communications.

[47]  M. E. Safar,et al.  Aortic Pulse Wave Velocity Predicts Cardiovascular Mortality in Subjects >70 Years of Age , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[48]  T. Pullar,et al.  Etanercept improves inflammation-associated arterial stiffness in rheumatoid arthritis. , 2009, Rheumatology.