Advanced glycation end products reduce the calcium transient in cardiomyocytes by increasing production of reactive oxygen species and nitric oxide

Abstract

Advanced glycation end products (AGE) are central to the development of cardiovascular complications associated with diabetes mellitus. AGE may alter cellular function through cross‐linking of cellular proteins or by activating the AGE receptor (RAGE). However, the signalling molecules involved during AGE stimulation in cardiomyocytes remain unclear. Here, we investigated the effects of AGE treatment on intracellular calcium homeostasis of isolated cardiomyocytes and studied the activation of signalling molecules involved in this process. Treatment of cardiomyocytes with AGE for 24 h resulted in a dose‐dependent reduction in calcium transient amplitude, reaching a maximum 50% reduction at a dose of 1 mg·mL−1. This was accompanied with a 32% reduction in sarcoplasmic reticulum calcium content but without any detectable changes in the expression of major calcium channels. Mechanistically, we observed a significant increase in the production of reactive oxygen species (ROS) in AGE‐treated cardiomyocytes and enhancement of NADPH oxidase activity. This was accompanied with activation of p38 kinase and nuclear translocation of NF‐κB, and subsequently induction of inducible NO synthase (iNOS) expression, leading to excessive nitric oxide production. Overall, our data reveal the molecular signalling that may underlie the alteration of intracellular calcium homeostasis in cardiac myocytes due to AGE stimulation. This may provide new insights into the pathophysiological mechanisms of the development of diabetic cardiomyopathy.

Inhibition of Advanced Glycation End Products Formation Attenuates Cardiac Electrical and Mechanical Remodeling and Vulnerability to Tachyarrhythmias in Diabetic Rats

“…A similar mechanism could explain why the restoration of prolonged APD by AG was mimicked by knockdown of the RAGE gene in HG-cultured cell model. On the other hand, RAGE activation has been shown to enhance nitric oxide production and cell damage by up-regulation of inducible nitric oxide synthase (Sumi and Ignarro, 2004;Hegab et al, 2017). However, a previous study showed no increase in nitric oxide production in STZ-induced diabetic rat hearts (Stadler et al, 2005), implicating that the protective effect of AG in the diabetic heart may not necessarily due to inducible nitric oxide synthase inhibition.…”

Reduced Susceptibility to Sugar‐Induced Metabolic Derangements and Impairments of Myocardial Redox Signaling in Mice Chronically Fed with D‐Tagatose when Compared to Fructose

“…Oxidative stress is a key factor in the pathophysiology of diet-related cardiovascular complications [ 36 , 37 ]. Very recently, RAGE activation, following binding with AGEs, has been shown to mediate oxidative stress in cardiomyocytes [ 38 ]. Here we confirmed that mice exposed to fructose, in both the liquid and solid formulations, exhibited a massive increase in myocardial oxidative stress, as suggested by markers of peroxidation of cell membrane lipids and radical-induced DNA damage as well as activity of antioxidant enzymes.…”

Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes

“…Upregulation of CD38 expression also signals maturation of dendritic cells during inflammatory cytokine activation and acts as a modulating adhesion and signaling molecule between dendritic cells and lymphocytes (105). In cardiomyocytes, exogenous stimulants may stimulate an increase in intracellular calcium, which leads to activation of CD38 (147). CD38 expression has also been shown to increase with age (65), and this is most likely attributed to an age-related increase in circulating inflammatory cytokines, and reduced CD38 function has been associated with poor immune responses.…”