Reduced acute vascular injury and atherosclerosis in hyperlipidemic mice transgenic for lysozyme.

Hyperlipidemia promotes oxidant stress, inflammation, and atherogenesis in apolipoprotein E-deficient (ApoE((-/-))) mice. Mice transgenic for lysozyme (LZ-Tg) are resistant to acute and chronic oxidative stress and have decreased circulating levels of pro-oxidant advanced glycation end-products (AGEs). Herein we report that TIB-186 macrophages transduced with adenovirus-expressing human LZ (AdV-LZ) containing the AGE-binding domain facilitated AGE uptake and degradation and that AdV-LZ-transduced macrophages and peritoneal macrophages from LZ-Tg mice suppressed the AGE-triggered tumor necrosis factor-alpha response. We assessed atherosclerosis in LZ-Tg mice crossed with ApoE((-/-)) mice (LZ/ApoE((-/-))) and found increased serum LZ levels and decreased AGE and 8-isoprostanes levels, although hyperlipidemia remained similar to ApoE((-/-)) controls. Atherosclerotic plaques and neointimal lesions at the aortic root and descending aorta were markedly decreased (by 40% and 80%, respectively) in LZ/ApoE((-/-)) versus ApoE((-/-)) mice, as were inflammatory infiltrates. The arterial lesions following femoral artery injury in LZ/ApoE((-/-)) mice were suppressed (intimal to media ratio decreased by 50%), as were AGE deposits and vascular smooth muscle cell activation, compared to ApoE((-/-)) mice. Despite hyperlipidemia, development of atheroma and occlusive, inflammatory arterial neointimal lesions in response to injury was suppressed in LZ/ApoE((-/-)) mice. This effect may be due to the antioxidant properties of LZ, which is possibly linked to the AGE-binding domain region of the molecule.

[1]  G. Striker,et al.  Amelioration of oxidant stress by the defensin lysozyme. , 2006, American journal of physiology. Endocrinology and metabolism.

[2]  J. Coresh,et al.  Glycemic control, atherosclerosis, and risk factors for cardiovascular disease in individuals with diabetes: the atherosclerosis risk in communities study. , 2005, Diabetes care.

[3]  J. Uribarri,et al.  Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. , 2005, Diabetes.

[4]  S. Minucci,et al.  Electron Transfer between Cytochrome c and p66Shc Generates Reactive Oxygen Species that Trigger Mitochondrial Apoptosis , 2005, Cell.

[5]  F. Recchia,et al.  Role of oxidative-nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure. , 2005, Current vascular pharmacology.

[6]  J. Uribarri,et al.  Diet‐Derived Advanced Glycation End Products Are Major Contributors to the Body's AGE Pool and Induce Inflammation in Healthy Subjects , 2005, Annals of the New York Academy of Sciences.

[7]  H. Vlassara.  Advanced Glycation in Health and Disease: Role of the Modern Environment , 2005, Annals of the New York Academy of Sciences.

[8]  D. Lackland,et al.  Addressing the Global Cardiovascular Risk of Hypertension, Dyslipidemia, Diabetes Mellitus, and the Metabolic Syndrome in the Southeastern United States, Part II: Treatment Recommendations for Management of the Global Cardiovascular Risk of Hypertension, Dyslipidemia, Diabetes Mellitus, and the Meta , 2005, The American journal of the medical sciences.

[9]  D. Lackland,et al.  Addressing the global cardiovascular risk of hypertension, dyslipidemia, and insulin resistance in the southeastern United States. , 2005, The American journal of the medical sciences.

[10]  W. Stahl,et al.  Nutritional, dietary and postprandial oxidative stress. , 2005, The Journal of nutrition.

[11]  R. Ramasamy,et al.  RAGE Axis: Animal Models and Novel Insights Into the Vascular Complications of Diabetes , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[12]  M. Czaja,et al.  Hepatocyte Resistance to Oxidative Stress Is Dependent on Protein Kinase C-mediated Down-regulation of c-Jun/AP-1* , 2004, Journal of Biological Chemistry.

[13]  J. Uribarri,et al.  High Levels of Dietary Advanced Glycation End Products Transform Low-Dersity Lipoprotein Into a Potent Redox-Sensitive Mitogen-Activated Protein Kinase Stimulant in Diabetic Patients , 2004, Circulation.

[14]  Merlin C. Thomas,et al.  Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis. , 2004, Diabetes.

[15]  E. Stadtman.  Role of oxidant species in aging. , 2004, Current medicinal chemistry.

[16]  H. Bruunsgaard,et al.  Inflammatory mediators in the elderly , 2004, Experimental Gerontology.

[17]  S. Plevy,et al.  Inhibition of Interleukin-12 p40 Transcription and NF-κB Activation by Nitric Oxide in Murine Macrophages and Dendritic Cells* , 2004, Journal of Biological Chemistry.

[18]  B. Astor,et al.  Evidence for increased cardiovascular disease risk in patients with chronic kidney disease , 2004, Current opinion in nephrology and hypertension.

[19]  R. Ramasamy,et al.  Protein Glycation: A Firm Link to Endothelial Cell Dysfunction , 2004, Circulation research.

[20]  A. Januszewski,et al.  Role of lipids in chemical modification of proteins and development of complications in diabetes. , 2003, Biochemical Society transactions.

[21]  K. Griendling,et al.  Reactive oxygen species in the vasculature: molecular and cellular mechanisms. , 2003, Hypertension.

[22]  S. Vatner,et al.  Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. , 2003, American journal of physiology. Heart and circulatory physiology.

[23]  G. FitzGerald,et al.  Oxidative stress and cardiovascular injury: Part II: animal and human studies. , 2003, Circulation.

[24]  G. FitzGerald,et al.  Oxidative Stress and Cardiovascular Injury: Part I: Basic Mechanisms and In Vivo Monitoring of ROS , 2003, Circulation.

[25]  J. Uribarri,et al.  Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients. , 2003, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[26]  E. Fisher,et al.  Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. , 2003, Atherosclerosis.

[27]  Merlin C. Thomas,et al.  A Breaker of Advanced Glycation End Products Attenuates Diabetes‐Induced Myocardial Structural Changes , 2003, Circulation research.

[28]  Y. Epstein,et al.  Plasma antioxidant status and cell injury after severe physical exercise , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Andrassy,et al.  Central role of RAGE-dependent neointimal expansion in arterial restenosis. , 2003, The Journal of clinical investigation.

[30]  J. Uribarri,et al.  Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. , 2003, Journal of the American Society of Nephrology : JASN.

[31]  M. Peppa,et al.  Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  E. Fisher,et al.  Lowering of dietary advanced glycation endproducts (AGE) reduces neointimal formation after arterial injury in genetically hypercholesterolemic mice. , 2002, Atherosclerosis.

[33]  M. Peppa,et al.  Oxidative Stress-Inducing Carbonyl Compounds From Common Foods: Novel Mediators of Cellular Dysfunction , 2002, Molecular medicine.

[34]  M. Steffes,et al.  Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products , 2002, Diabetes/metabolism research and reviews.

[35]  R. Bucala,et al.  Lysozyme Enhances Renal Excretion of Advanced Glycation Endproducts In Vivo and Suppresses Adverse AGE-mediated Cellular Effects In Vitro: A Potential AGE Sequestration Therapy for Diabetic Nephropathy? , 2001, Molecular medicine.

[36]  V. D’Agati,et al.  Receptor for Advanced Glycation End Products Mediates Inflammation and Enhanced Expression of Tissue Factor in Vasculature of Diabetic Apolipoprotein E–Null Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[37]  J. Baynes,et al.  Glycoxidation and lipoxidation in atherogenesis. , 2000, Free radical biology & medicine.

[38]  R. Paules,et al.  Oxidative stress and cell cycle checkpoint function. , 2000, Free radical biology & medicine.

[39]  B. Demple,et al.  Genetic Responses to Free Radicals: Homeostasis and Gene Control , 2000, Annals of the New York Academy of Sciences.

[40]  H. Vlassara,et al.  Standardizing the immunological measurement of advanced glycation endproducts using normal human serum. , 1997, Journal of immunological methods.

[41]  H. Vlassara,et al.  Depletion of reactive advanced glycation endproducts from diabetic uremic sera using a lysozyme-linked matrix. , 1997, The Journal of clinical investigation.

[42]  E. Schleicher,et al.  Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. , 1997, The Journal of clinical investigation.

[43]  R. Bucala,et al.  Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Pope,et al.  Autocrine regulation of collagenase gene expression by TNF‐α in U937 cells , 1996, Journal of leukocyte biology.

[45]  Yong Ming Li,et al.  Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation–modified proteins to a conserved motif , 1995, Nature Medicine.

[46]  C. Goodnow,et al.  Induction of self-tolerance in T cells but not B cells of transgenic mice expressing little self antigen. , 1991, Science.

[47]  K. Meyer,et al.  ON THE MECHANISM OF LYSOZYME ACTION , 1936 .

[48]  Qin M. Chen,et al.  Linking oxidative stress and genetics of aging with p66Shc signaling and forkhead transcription factors , 2004, Biogerontology.

[49]  A. Cripps,et al.  Measurement of lysozyme by an enzyme-linked immunosorbent assay. , 1992, Journal of immunological methods.