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(Circulation Research. 2003;92:704.)
© 2003 American Heart Association, Inc.

Editorials

Getting Better Without AGE

New Insights Into the Diabetic Heart

David A. Kass

From the Johns Hopkins University, Baltimore, Md.

Correspondence to David A. Kass, Division of Cardiology, Johns Hopkins University, Halsted 500, 600 N Wolfe St, Baltimore, MD 21287. E-mail dkass@jhmi.edu

Key Words: AGE • collagen • diabetes • RAGE • heart

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Nearly a century ago, Maillard first observed that incubation of glucose with amino acids led to the formation of a yellow-brown pigment due to nonenzymatic glycosylation.¹ This unstable compound known as a Schiff base can undergo rearrangement over several days to form the more stable Amadori-type product.² One well-known example is hemoglobin A_1C, the adduct of glucose with the N-terminal valine amino group of the ß-chain of hemoglobin.³ This process of nonenzymatic protein glycation differs from enzyme-dependent o-glycosylation, the latter being a reversible process whereby proteins are modified at specific residues to effect signal transduction much like phosphorylation.R4-128042 ^4,5 Glycated proteins, in contrast, can further evolve over time, undergoing complex rearrangements to yield crosslinked proteins known as advanced glycation end products (AGEs)R2-128042 ^2,6 (Figure). Importantly, and in contrast to Amadori product precursors, AGEs are virtually irreversible once formed. Long-lived structural proteins such as collagen are particularly vulnerable to AGE crosslinks by nature of their slow turnover rate.⁷

View larger version (49K): [in this window] [in a new window]   Pathophysiology of advanced glycation end products (AGEs). Glucose interacts over several hours with reactive amino groups on proteins to form the unstable and reversible Schiff base. Over longer periods of time (days), this can further develop into an Amadori product, a more stable form of protein glycation. Over periods of months to years, these glycated proteins can undergo further complex rearrangement to generate AGEs. AGEs can serve themselves as signaling molecules, interacting with specific receptors (ie, RAGE), which triggers a broad array of stress and oxidant response signaling, as well as develop . . . [Full Text of this Article]

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