Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression

Abstract

Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I) can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE Nɛ-(1-carboxymethyl)lysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation.

Plasma Advanced Glycation End Products Are Associated With Incident Cardiovascular Events in Individuals With Type 2 Diabetes: A Case-Cohort Study With a Median Follow-up of 10 Years (EPIC-NL)

“…We consistently found that CEL in particular was strongly associated with incident cardiovascular events. This finding is in line with the concept that methylglyoxal and its derived AGEs, such as CEL, play the most important role in AGE accumulation (1) and development of diabetes complications (34,35). However, this finding should be interpreted with some caution, as for CML and pentosidine, we are likely to underestimate associations with outcome due to residual negative confounding from obesity, as BMI (or waist circumference) does not completely capture adiposity.…”

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

“…In a rat model of type 1 diabetes, it has been shown that MGO reduces the ability of SERCA2a to perform this translocation, resulting in diastolic dysfunction of the heart [170]. It is interesting that the overexpression of GLO1 does attenuate mild oxidative damage in the diabetic rat heart, by reducing MGO levels [171].…”

Dicarbonyl Stress and Glyoxalase-1 in Skeletal Muscle: Implications for Insulin Resistance and Type 2 Diabetes

“…Alternatively, MG can form from lipid peroxidation mechanisms, known to be exacerbated with oxidative stress, a common characteristic of insulin resistance and T2DM ( 13 ). MG induces pathways known to contribute to insulin resistance including: (1) oxidative stress caused by damage to mitochondria ( 31 ) and mitochondrial DNA ( 32 ), (2) generation of AGEs [for more information on the independent effects of AGEs in diabetes and diabetic complications, the reader is directed to a recent review by Brings et al ( 33 )] and (3) inflammation mediated through the Receptor for Advanced Glycation Endproducts (RAGE) signaling ( 34 – 36 ). RAGE is highly expressed in skeletal muscle ( 37 , 38 ) and upon binding of a RAGE-ligands (i.e., MG-H1) a well characterized inflammatory signaling cascade ensues ( 39 – 41 ).…”