Reducing
sugars can react non-enzymatically with the amino groups of
proteins to form reversible
Schiff bases, and then Amadori products. These early glycation products undergo further complex reactions such as rearrangement,
dehydration and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives termed "
advanced glycation end products" (AGEs). The pathological role of the non-enzymatic glycation of
proteins has become increasingly evident in various types of disorders such as
diabetic vascular complications,
neurodegenerative diseases, and
melanoma growth and
metastasis. Furthermore, there is a growing body of evidence that RAGE is a signal-transducing receptor for AGEs and that engagement of RAGE with AGEs evokes oxidative stress and vascular
inflammation, thereby being involved in the AGE-related disorders. We have recently found that
atorvastatin, a
lipid-lowering agent decreases serum levels of AGEs in type 2 diabetic patients in a
cholesterol-lowering independent manner. Further, we have shown that atorvastain blocks the AGE-signaling to
C-reactive protein (CRP) expression in human
hepatoma cells in vitro via anti-oxidative properties. These observations led us to speculate that
atorvastatin could be a promising remedy for treating patients with AGE-related disorders. In this paper, we would like to propose the possible ways of testing our hypotheses. (1) Does
atorvastatin treatment reduce the development and progression of
diabetic vascular complications with normocholesterolemic patients? If the answer is yes, is this beneficial effect of
atorvastatin superior to that of other
cholesterol-lowering agents with equihypolipidemic properties? (2) Are these beneficial effects of atorvastain attributed to its AGE-lowing properties? Does the blockade by atorvastain of the AGE signaling pathway, in other words, the suppression of
8-hydroxydeoxyguanosine and CRP levels by
atorvastatin treatment, contribute to its cardioprotective properties? (3) Does the treatment with
atorvastatin decrease the incidence of
neurodegenerative disorders such as
Alzheimer's disease and/or prolong the survival of these patients? (4) How about the effects of
atorvastatin on the incidence of
malignant melanoma? These prospective studies will provide further valuable information whether the blockade by
atorvastatin of the AGE formation or the AGE-downstream signaling could be clinically relevant.