Glycation in the cardiomyocyte

Abstract

Glycation is a protein post-translational modification that can occur on lysine and arginine residues as a result of a non-enzymatic process known as the Maillard reaction. This modification is irreversible, so the only way it can be removed is by protein degradation and replacement. Small reactive carbonyl species, glyoxal and methylglyoxal, are the primary glycating agents and are elevated in several conditions associated with an increased risk of cardiovascular disease, including diabetes, rheumatoid arthritis, smoking, and aging. Thus, how protein glycation impacts the cardiomyocyte is of particular interest, to both understand how these conditions increase the risk of cardiovascular disease and how glycation might be targeted therapeutically. Glycation can affect the cardiomyocyte through extracellular mechanisms, including RAGE-based signaling, glycation of the extracellular matrix that modifies the mechanical environment, and signaling from the vasculature. Intracellular glycation of the cardiomyocyte can impact calcium handling, protein quality control and cell death pathways, as well as the cytoskeleton, resulting in a blunted contractility. While reducing protein glycation and its impact on the heart has been an active area of drug development, multiple clinical trials have had mixed results and these compounds have not been translated to the clinic-highlighting the challenges of modulating myocyte glycation. Here we will review protein glycation and its effects on the cardiomyocyte, therapeutic attempts to reverse these, and offer insight as to the future of glycation studies and patient treatment.

Keywords: Advanced glycation end-products (AGEs); Cardiomyocyte; Glycation; Glyoxalase; Post-translational modification (PTM); Protein quality control (PQC); Receptors for advanced glycation end-products (RAGE) Note: Also called AGER; Sarcomere.

Figure 1.. Glycation targets reactive PTMs and is usually taken care of with glyoxalase cycle.

(A) Three examples of glycation: Methylglyoxal and lysine reacting to form CEL (left); methylglyoxal and arginine reacting to form MG-H1 (middle); ribose reacting with lysine and arginine to form pentosidine (right). (B) Diagram of the glyoxalase cycle. Glyoxalase 1 and 2 turn methylglyoxal into D-Lactate, utilizing and regenerating GSH in the process.

Figure 2.. Calcium handling of cardiomyocytes is disrupted by both intra- and extracellular glycation.

A: Normal calcium handling in the cardiomyocyte. To be compared with B and C B: Example of the effect RAGE signaling has on calcium handling in the cardiomyocyte C: Example of the effect intracellular AGEs have on the cardiomyocyte

Figure 3.. Glycation of the myofilament is detrimental to cardiomyocyte function.

(A-B) Diagram of the sarcomere and the effect AGE generation has on sarcomere function (C) Sequence analysis of glycated peptides indicating no consensus sequence for glycation (D) Glycation of the thick and thin filament proteins, highlighting actin and myosin glycation (E) Glycation of the thick filament (F) Glycation of the thin filament

Figure 4.

Diagram of known AGE-induced PQC disruption in cardiomyocytes

Figure 5.. Attempts at treating glycation have been largely unsuccessful, but remain under investigation.

(A) The mechanism of Alagebrium, an AGE-breaker (B) The mechanism of aminoguanidine, an AGE-inhibitor (C) The theory behind Glo1 overexpression in reducing glycation