INTRODUCCIÓN: REVISIÓN CRITICA DEL PROBLEMA

Introduction
ANEXOS
Diabetes mellitus, which is one of the main causes of mortality and morbidity in
occidental countries, is strongly linked to several cardiovascular complications 1 .
Under the condition of prolonged hyperglycemia as in diabetes advanced glycatio
end-products (AGE) are formed 2 . Firstly, the basic aminoacids of proteins are
modified by glucose to form Schiff bases. These bases evolve to Amadori
products, which undergo additional chemical rearrangements to form irreversibly
AGE 3 . Amadori products are found in 2-10 times higher concentration than AGE 4 .
These intermediate glycated products, although less studied than AGE, have been
related ith oxidative stress and cardiovascular diseases 5-6 .
Oxidative stress happens when the reactive oxygen species (ROS) exceed the
protective antioxidant systems and this stress is directly related with endothelial
dysfunction 7 . NADPH oxidase is the most important source of ROS in the
endothelium in case of hypertension, inflammation and ischemia-reperfusion
injury 8 . NADPH oxidase is a multimeric enzyme firstly found in phagocytes,
consisting on the membrane catalytic subunit gp91phox (NOX2) bound to
P22PHOX and associated with several cytosolic regulatory subunits. There are
numerous homologues of gp91phox named NOX1, NOX3, NOX4 and NOX5,
where NOX4 is the most abundant isoform in the endothelium 9 .
Previous studies have shown increased ROS production induced by glycated
Amadori-albumin and related with NADPH oxidase. Glycated bovine albumin
increased superoxide anion production in quiescent human mesangial cells, and
this increase was inhibited by diphenyleneiodonium (DPI), an inhibitor of NADPH
oxidase 10 . Human umbilical vein endothelial cells (HUVEC) treated with glycated
albumin showed both E-selectin and ROS increased production depending on
NADPH oxidase 11 . In a previous study, we have reported a glycated human serum
albumin (gHSA) induced superoxide anion production increment in HUVEC by an
up-regulation enhancement of NOX4 and P22PHOX expression 5 .
It is still unclear the molecular signaling pathways activated by glycated albumin
which lead to these effects, but some of them stand out. Mitogen-activated protein
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