Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity

Abstract

New Findings What is the central question of this study?Does acute exposure to high molecular weight advanced glycation end products (HMW‐AGEs) alter cardiomyocyte contractile function? What is the main finding and its importance?Ventricular cardiomyocytes display reduced Ca2+ influx, resulting in reduced contractile capacity, after acute exposure to HMW‐AGEs, independent of activation of their receptor. Given that HMW‐AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds. Abstract Sustained elevated levels of high molecular weight advanced glycation end products (HMW‐AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW‐AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre‐incubated with or without an anti‐RAGE antibody. Unloaded cell shortening and L‐type Ca2+ current amplitude were evaluated in the presence or absence of HMW‐AGEs (200 μg ml−1). Expression of RAGE, c‐Jun N‐terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW‐AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca2+ influx. These alterations were also observed in cardiomyocytes pre‐incubated with anti‐RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW‐AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation.

The Impact of Advanced Glycation End-Products (AGEs) on Proliferation and Apoptosis of Primary Stem Cells: A Systematic Review

“…Furthermore, it has been shown that AGEs have an important role in the pathophysiology of different complications of diabetes mellitus, e.g., cardiomyopathy, retinopathy, neuropathy, and nephropathy [26]. Additionally, in cardiovascular diseases [27], Alzheimer's disease, and cancer, AGEs have been proven to display a causative role [28]. They can accumulate throughout the body in various tissues such as in the heart [29], blood vessels [30], lungs [31], and adipose tissue [32], exerting long-term effects.…”

Glycolaldehyde-modified proteins cause adverse functional and structural aortic remodeling leading to cardiac pressure overload

“…Whether HMW-AGEs strengthen contraction by disturbing downstream α1 adrenergic signaling factors like phospholipase C, inositol trisphosphate or calcium deserves further investigation. Results from our research group demonstrated that HMW-AGEs indeed disturb calcium homeostasis in cardiomyocytes 34 . HMW-AGEs possibly disturb calcium homeostasis in endothelial or vascular smooth muscle cells as well, which has been shown before following acute exposure to the AGEs precursor methylglyoxal 32 , 35 .…”

Glycolaldehyde-Derived High-Molecular-Weight Advanced Glycation End-Products Induce Cardiac Dysfunction through Structural and Functional Remodeling of Cardiomyocytes

“…After six weeks of daily injections, conventional echocardiographic images were obtained in rats anesthetized via inhalation with 3% isoflurane supplemented with oxygen as described previously [16] and invasive hemodynamic measurements were performed. Finally, the heart was harvested and left ventricular (LV) single cardiomyocytes were isolated, as previously described [14]. Tissue of both animal groups was fixed overnight with 2% glutaraldehyde in 0.05 M cacodylate buffer at 4°C for light microscopic (LM) and electron microscopic (EM) examination or were fixed overnight in 4% paraformaldehyde and transferred in 70% ethanol until embedded in paraffin.…”

“…Hearts were dissected and weighted. Single adult cardiomyocytes from the LV were obtained by enzymatic dissociation through retrograde perfusion of the aorta, as previously described [14]. The hearts were perfused with normal Tyrode (NT) (in mM, NaCl 137, KCl 5.4, MgCl 2 0.5, CaCl 2 1, Na-HEPES 11.8, glucose 10 and taurine 20; pH 7.35) on a Langendorff setup at 37°C.…”

“…While most of these studies focus primarily on LMW-AGEs, very little is reported on HMW-AGEs. However, their importance in cardiac pathophysiology is rising [13,14]. We have previously shown that HMW-AGEs are responsible for cardiac dysfunction (i.e.…”