Potential therapeutic implication of nifedipine, a dihydropyridine-based calcium antagonist, in advanced glycation end product (AGE)-related disorders

Abstract

A non-enzymatic reaction between ketones or aldehydes and the amino groups of proteins contributes to the aging of proteins and to pathological complications of diabetes. Under hyperglycemic conditions in diabetes, this process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions and rearrangements to become irreversible crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). Recent understanding of this process has confirmed that AGE-their receptor (RAGE) interaction-elicited oxidative stress generation was implicated in the pathogenesis of diabetic vascular complication, melanoma growth, expansion and metastasis. We have recently found that nifedipine, one of the most widely used dihydropyridine-based calcium antagonists (DHPs) for treatments of patients with angina pectoris and hypertension, inhibited RAGE overexpression in AGE-exposed endothelial cells by suppressing reactive oxygen species generation. Since RAGE is a signal-transducing receptor for AGEs and subsequently evokes inflammatory responses in various types of cells, thus eliciting angiogenesis and thrombogenesis, we hypothesize here that blockade of RAGE expression by nifedipine may have therapeutic potentials in treatment of patients with various AGE-related disorders. In this paper, we would like to propose the possible ways of testing our hypothesis. Does nifedipine treatment reduce the development and progression of diabetic vascular complications? If the answer is yes, is this beneficial effect of nifedipine superior than that of other DHPs with equihypotensive properties? Does nifedipine treatment decrease the incidence of melanoma and/or prolong the survival of patients with this devastating disorder? These prospective studies will provide further valuable information whether blockade by nifedipine of the AGE-RAGE signaling could be clinically relevant.