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Advanced Glycation End Products

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Half-life of an AGE is double that of an erythrocyte. AGEs in the Body ... But, AGE inhibitors needs to be further studied in human clinical trials. ... – PowerPoint PPT presentation

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Title: Advanced Glycation End Products


1
Advanced Glycation End Products
Andreea Deaconu - andreea.deaconu_at_utoronto.ca Avi
Silver - avi.silver_at_utoronto.ca Hoi-Man Leung -
dorothy.leung_at_utoronto.ca Joshua Smith -
joshd.smith_at_utoronto.ca March 4, 2009
2
AGEs An Overview
  • Advanced Glycation End Products
  • Formed from the reaction of sugar molecule with
    either a protein or lipid molecule without
    enzymatic control
  • non-enzymatic glycosylation
  • Comes from exogenous sources (ie diet, tobacco
    smoke) and endogenous sources via normal
    metabolism and aging
  • High levels of AGEs is implicated in many chronic
    diseases

3
Examples of AGEs
Basta, G., Schmidt, A. M., De Caterina, R.
(2004). Advanced glycation end products and
vascular inflammation implications for
accelerated atherosclerosis in diabetes.
Cardiovascular Research, 63, 582-592.
4
Exogenous Sources of AGE Diet
  • Heating of food can create reactive AGE products
    by accelerating glycation
  • Food manufacturers enhance natural flavours by
    incorporating synthetic AGEs into foods
  • Foods with significant browning, caramelization
  • e.g. donuts

5
Exogenous Sources of AGE Diet
  • Quantity of AGEs consumed has increased
    significantly in last 50 years
  • Direct correlation between serum AGE levels and
    AGE consumed
  • Suggesting a relationship between high dietary
    AGE intake and development/progression of
    diabetes-related damage

6
AGEs in the Body
  • Small proportion of ingested simple sugars
    undergo glycation mainly in the bloodstream
  • Intracellular natural sugars (ie
    glyceraldehyde-3-phosphate, fructose) react 10
    times faster than glucose
  • Lead to the release of highly oxidizing
    side-products such as hydrogen peroxide
  • Half-life of an AGE is double that of an
    erythrocyte

7
AGEs in the Body
  • Undergo renal clearance at a very slow rate
  • Affect nearly every type of cell and molecule in
    the body
  • Direct damage to myelin sheath, fibrinogen,
    collagen or endothelial cells
  • Indirectly affect body function through
    side-products formed in the reaction leading to
    AGEs

8
Receptor of Advanced Glycation End Products
(RAGE)?
9
What is RAGE?
  • Originally isolated from bovine lung and found to
    be present on endothelial cells, where it
    mediates the binding of AGEs
  • A 35-kDa polypeptide transmembrane receptor of
    the immunoglobin superfamily of cell surface
    molecules with a unique NH2-terminal sequence
  • RAGE may bind to other ligands aside from AGE.
  • Amphoterin
  • S110b
  • Pattern Recognition Receptor.

10
Structure of RAGE
  • The receptor consists of 5 domains
  • Cytosolic domain responsible for signal
    transduction
  • Transmembrane domain anchors the receptor in the
    cell membrane
  • Variable domain binds the RAGE ligands
  • 2 Constant domains
  • There is a short highly charged cytosolic tail of
    43 amino acids, which is necessary for signalling

11
RAGE
  • Aside from endothelial cells, RAGE may be
    expressed by monocytes/macrophages, neurons and a
    range of other cells whose dysfunction has been
    linked to many chronic disorders
  • These include
  • Diabetes specifically the vascular complications
  • Alzheimers disease
  • Inflammation
  • Atherosclerosis

12
RAGE
  • Binding of ligands to RAGE triggers signal
    transduction mechanisms
  • including formation of lipid peroxides, and
    activation of NF-?B (a protein complex that acts
    as a transcription factor)?
  • Activation of NF-?B leads to subsequent gene
    expression regulated by NF-?B
  • Over-expression of NF-?B has been linked to
    cancer, inflammatory and autoimmune diseases
  • In addition, ligands of RAGE might induce NF-?B
    co-activators that support and enhance sustained
    NF-?B activation

13
Pathways in AGE Formation
Basta, G., Schmidt, A. M., De Caterina, R.
(2004). Advanced glycation end products and
vascular inflammation implications for
accelerated atherosclerosis in diabetes.
Cardiovascular Research, 63, 582-592.
14
Pathways in AGE Formation
  • Glucose and other reducing sugars react
    nonenzymatically with protein amino groups.
  • Leading to formation of Schiff Bases and Amadori
    Products
  • Amadori products are highly reactive intermediate
    carbonyl groups that can accumulate or
  • React with lysine and arginine functional groups
    on proteins, to form irreversibly bound AGEs.

15
Role of AGE in Disease States
  • Based on 2 general mechanisms
  • Formation of cross-links between key molecules in
    the basement membrane of the extracellular matrix
    (ECM)?
  • Interaction of AGEs and the RAGE on cell surfaces
    which alters cellular functions

16
Accelerated Atherosclerosis in Diabetes
  • Associated with the accumulation of AGEs in the
    ECM and within cells of the vessel wall
  • Leading to formation of cross-bridges among
    vessel wall macromolecules resulting arterial
    stiffening and loss of elasticity
  • Modifying LDL cholesterol, leading to oxidation
    and plaque formation
  • Causing the circulating blood cells to adhere to
    vessel wall

17
Accelerated Atherosclerosis in Diabetes
  • Associated with RAGE-ligand interaction within
    the vasculature
  • Causing the induction of intracellular reactive
    oxygen species (ROS)?
  • Linked to the activation of the NAD(P)H-oxidase
    system and and NF-?B
  • Leads to transcriptional activation of many genes
    relevant for atherosclerosis such as tumor
    necrosis factors (TNF-a and TNF-h), interleukins
    1, 6 and 8 (IL-1, IL-6 and IL-8), interferon-g
    (IFN-g), and cell adhesion molecules

18
Role of AGE in Other Disease States
  • Evidence suggests the AGEs are mediators of
    nearly all diabetes complications
  • Example Retinopahy
  • AGES found in retinal vessels of diabetics
    patients
  • Levels of AGEs correlate well with the severity
    of retinopathy present.
  • Example Nephropathy
  • See characteristic thickening of glomerular
    membrane and accumulation of AGEs
  • Results in glomerulosclerosis and fibrosis in the
    kidneys

19
Nonpharmacological Therapies
  • Dietary Considerations
  • Minimize intake of foods high in AGE such as
    meat, cheese, egg yolk
  • Decreased cooking temperature
  • Broiling and frying can lead to increased amount
    of AGEs

20
Pharmacological Therapies
  • AGE Inhibitors e.g. Aminoguanidine
  • Prevents necessary glycation reactions for
    crosslinking
  • Animal studies have shown Aminoguanidine to
    prevent diabetic retinopathy, and nephropathy by
    decreasing AGE accumulation
  • But, AGE inhibitors needs to be further studied
    in human clinical trials.

21
Pharmacological Therapies
  • AGE-breakers
  • AGE inhibitors may not be effective in tissues
    with extensive AGE accumulation
  • AGE-breakers have been shown to reverse arterial
    stiffening, and disrupt already formed AGE by
    breaking established crosslinks
  • e.g. ALT-711, a new thiazolium derivative,
    3-phenyacyl-4,5-dimethylthiazolium chloride

22
Pharmacological Therapies
  • ALT-711
  • Catalytically breaks established AGE crosslinks
    between proteins to
  • Reduce arterial stiffening,
  • Enhance cardiac output,
  • Improve left ventricular diastolic distensibility
    in experimental animals
  • Shown to improve arterial compliance and reduces
    arterial pulse pressure in older individuals with
    a stiffened vasculature

23
Pharmacological Therapies
  • sRAGE Soluble form of RAGE
  • Extracellular ligand-binding domain of RAGE
  • Blocks AGEs from binding to RAGE
  • Suppresses accelerated formation of
    atherosclerotic lesion
  • Decreases vascular hyperpermeability
  • However, further clinical studies need to be
    done, in order to understand the full scope of
    AGE and RAGE biochemistry and function.

24
Summary
  • Advanced glycation end products (AGE) are derived
    from the nonenzymatic reaction of reducing sugars
    with free amino groups of proteins, lipids, and
    nucleic acids.
  • Schiff Bases and Amadori products are two
    immediates formed.
  • Receptor for advanced glycation endproducts
    (RAGE) is responsible for intracellular
    signalling that can disrupt cellular function.
  • AGE crosslinkages and AGE-RAGE interaction have
    been implicated in many disease states.
  • Many Anti-AGE therapies are being studied
    AGE-inhibitors, AGE-breakers and sRAGE.

25
References
  • Asif, M., Egan, J., Vasan, S. Lopez, S.
    (2000). An advanced glycation end product
    cross-link breaker can reverse age-related
    increases in myocardial stiffness. Proceedings of
    the National Academy of Sciences of the United
    States of America, 97(6), 2809-2813.
  • Basta, G., Schmidt, A. M., De Caterina, R.
    (2004). Advanced glycation end products and
    vascular inflammation implications for
    accelerated atherosclerosis in diabetes.
    Cardiovascular Research, 63, 582-592.
  • Bierhaus, A, et al. (2001). Diabetes-Associated
    Sustained Activation of the Transcription Factor
    Nuclear Factor NF-?B. Diabetes, 50(12), 2792-808.
  • Goldin, A., Beckman, J. A., Schmidt, A.M.,
    Creager, M. A. (2006). Advanced glycation end
    products sparking the development of diabetic
    vascular injury. Circulation, 114, 597-605.
  • Hudson, B.I., et al. (2002). Glycation and
    Diabetes The RAGE Connection. Current Science,
    83(12), 1515-1521.
  • Kass, D. A., Shapiro, E. P., Kawaguichi, M.,
    Capriotti, A. R., Scuteri, A., DeGroff, R. C.
    Lakatta, E. G. (2001). Improved arterial
    compliance by a novel advanced glycation
    end-product crosslink breaker. Circulation, 104
    (13), 1464-1470.
  • Neeper, M, et al. (1992). Cloning and Expression
    of a Cell Surface Receptor for Advanced
    Glycosylation End Products of Proteins. The
    Journal of Biological Chemistry, 267(21),
    4998-5004.
  • Peppa, M., Uribarri, J., Vlassara, H. (2003).
    Glucose, advanced glycation end products, and
    diabetes complications what is new and what
    works. Clinical Diabetes, 21(4), 186-187.
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