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

Abstract

Growing evidence supports the role of advanced glycation end products (AGEs) in the development of diabetic vascular complications and cardiovascular diseases (CVDs). We have shown that high-molecular-weight AGEs (HMW-AGEs), present in our Western diet, impair cardiac function. Whether HMW-AGEs affect vascular function remains unknown. In this study, we aimed to investigate the impact of chronic HMW-AGEs exposure on vascular function and structure. Adult male Sprague Dawley rats were daily injected with HMW-AGEs or control solution for 6 weeks. HMW-AGEs animals showed intracardiac pressure overload, characterized by increased systolic and mean pressures. The contraction response to PE was increased in aortic rings from the HMW-AGEs group. Relaxation in response to ACh, but not SNP, was impaired by HMW-AGEs. This was associated with reduced plasma cyclic GMP levels. SOD restored ACh-induced relaxation of HMW-AGEs animals to control levels, accompanied by a reduced half-maximal effective dose (EC 50 ). Finally, collagen deposition and intima-media thickness of the aortic vessel wall were increased with HMW-AGEs. Our data demonstrate that chronic HMW-AGEs exposure causes adverse vascular remodelling. This is characterised by disturbed vasomotor function due to increased oxidative stress and structural changes in the aorta, suggesting an important contribution of HMW-AGEs in the development of CVDs.

Acute Exposure to Glycated Proteins Impaired in the Endothelium-Dependent Aortic Relaxation: A Matter of Oxidative Stress

“…Interestingly, the accumulation of superoxide has been shown to be the cause of the attenuated endothelium-related relaxation capacity in diabetic rat aortae [ 44 ]. Furthermore, our group demonstrated previously that impaired endothelium-dependent relaxation caused by sustained increased levels of HMW-AGEs is mediated by an increased superoxide formation [ 25 ]. In the current study, we show that SOD improves the endothelium-dependent relaxation in aortic rings that are acutely preincubated with HMW-AGEs.…”

“…However, it should be noted that the vascular NO content also relies on the activity of the NO-producing enzyme eNOS [ 50 ]. The recent work of our group showed that the impaired aortic relaxation observed after chronic HMW-AGE exposure is not due to reduced eNOS activity [ 25 ]. In that context, the underlying mechanisms of AGEs for vascular dysfunction can differ between acute and chronic circumstances.…”

“…At the cellular level, chronic exposure to high levels of HMW-AGEs induces cardiomyocyte remodelling, resulting in impaired cellular function [ 24 ]. In addition, we have previously shown that the chronic administration of HMW-AGEs disturbs the vasomotor balance in rat aortae which is the result of increased oxidative stress [ 25 ].…”

Combinational Therapy of Cardiac Atrial Appendage Stem Cells and Pyridoxamine: The Road to Cardiac Repair?

“…Invasive hemodynamic measurements were obtained at sacrifice under 2% isoflurane anesthesia supplemented with oxygen, as described before [57]. Hemodynamic parameters were measured with an SPR-320 Mikro-Tip single pressure catheter (Millar Inc., The Hague, The Netherlands) placed into the LV via the right carotid artery.…”

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

“…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.…”