Biomedical Engineering Reference
In-Depth Information
takes considerably longer, requiring up to several days. Schiff bases and Amadori
products represent the so-called early glycation products and are used clinically to
assess glycemic control of patients (typically glycated hemoglobin or HbA1c).
Importantly, these early products are also the precursors to AGE formation and
accumulation. The Amadori products breakdown to give rise to highly reactive
a-dicarbonyl glyoxal compounds also known as a-oxoaldehyde, such as methyl-
glyoxal, glyoxal and 3-deoxyglucosone. Increased synthesis of these by-products
can give rise to carbonyl stress [ 143 ]. a-oxoaldehydes can be used in vitro as a
mechanism for forming AGEs over a matter of days. Dehydration of Amadori
products can lead to the formation of Amadori diones and Amadori ene-dione.
These reactive intermediates from the ''Maillard reaction'' can then lead to the
accumulation of more AGE and protein cross-links [ 144 ]. In vivo, a time frame of
often weeks to months is required for the Amadori products to rearrange crosslink
and form AGE compounds.
AGE formation on ECM proteins has been demonstrated for a number of proteins
including collagen, elastin and fibronectin possibly disrupting normal ECM protein-
integrin interactions. As mentioned earlier, ECM proteins allow cells to communi-
cate and react with extracellular environment via both inside-out and outside-in
signaling [ 145 ]. These ECM components are also major contributors to the ''visco-
elastic'' properties of the vessel walls and contribute to the regulation of vessel
diameter [ 146 ]. ECM-integrin interactions can also impact vascular remodeling and
permeability [ 145 , 147 , 148 ]. AGE formation alters other characteristics of ECM
proteins including inhibiting their turnover via matrix metalloproteinases [ 149 , 150 ].
This may contribute to apparent increased matrix protein deposition (see below) and
contribute to vascular remodeling [ 151 ]. Thus glycation of ECM proteins can alter
cellular structure and function by altered signaling and forming protein cross-links
which in turn can lead to aberrant vasoregulation and increased arterial stiffness in
diabetes.
An additional consideration is that AGEs bind a cell surface receptor (RAGE;
receptor for advance glycation endproducts), which is a multi-ligand member of
the immunoglobulin superfamily. Activation of RAGE can initiate intracellular
signaling pathways including NADPH oxidase, MAP kinase and NfjB, which
impact a variety of cellular events including gene expression and the release of
pro-inflammatory molecules such as IL-a, IL-6, and TNF-a [ 152 ]. There is also an
increase in inflammation in the vasculature due to enhanced reactive oxygen
species (ROS) through the activation of NADPH oxidase [ 153 - 156 ]. AGE-RAGE
interactions lead to augmented proliferative and migratory pathways in SMCs and
can lead to neo-intimal expansion and ECM production [ 157 , 158 ]. In addition to
RAGE interactions, glycation of fibronectin increases binding/adhesion of the
protein to VSMCs as assessed by atomic force microscopy [ 159 ] in part through
altered binding to cell surface integrins. Glycation of fibronectin also decreases the
normal fibronectin-induced activation of VSMC K + channels.). Collectively,
RAGE-activated pathways add to diabetes-induced vasculopathy via multiple
different mechanisms.
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