Receptor for Advanced Glycation End-Products Signaling Interferes with the Vascular Smooth Muscle Cell Contractile Phenotype and Function

Abstract

Increased blood glucose concentrations promote reactions between glucose and proteins to form advanced glycation end-products (AGE). Circulating AGE in the blood plasma can activate the receptor for advanced end-products (RAGE), which is present on both endothelial and vascular smooth muscle cells (VSMC). RAGE exhibits a complex signaling that involves small G-proteins and mitogen activated protein kinases (MAPK), which lead to increased nuclear factor kappa B (NF-κB) activity. While RAGE signaling has been previously addressed in endothelial cells, little is known regarding its impact on the function of VSMC. Therefore, we hypothesized that RAGE signaling leads to alterations in the mechanical and functional properties of VSMC, which could contribute to complications associated with diabetes. We demonstrated that RAGE is expressed and functional in the A7r5 VSMC model, and its activation by AGE significantly increased NF-κB activity, which is known to interfere with the contractile phenotype of VSMC. The protein levels of the contraction-related transcription factor myocardin were also decreased by RAGE activation with a concomitant decrease in the mRNA and protein levels of transgelin (SM-22α), a regulator of VSMC contraction. Interestingly, we demonstrated that RAGE activation increased the overall cell rigidity, an effect that can be related to an increase in myosin activity. Finally, although RAGE stimulation amplified calcium signaling and slightly myosin activity in VSMC challenged with vasopressin, their contractile capacity was negatively affected. Overall, RAGE activation in VSMC could represent a keystone in the development of vascular diseases associated with diabetes by interfering with the contractile phenotype of VSMC through the modification of their mechanical and functional properties.

Advanced Glycation End Products Impair Ca2+ Mobilization and Sensitization in Colonic Smooth Muscle Cells via the CAMP/PKA Pathway

“…An accelerated expression of RAGE mediated by AGE may contribute to oxidative stress, which plays a key role in the pathogenesis of diabetic complications [44,45]. In human cardiomyocytes, blocking RAGE with anti-RAGE IgG completely abolished the AGE-induced depletion of sarcoplasmic reticulum Ca 2+ content, which may contribute to contractile dysfunction in diabetic cardiomyopathy [46].…”

iRAGE as a novel carboxymethylated peptide that prevents advanced glycation end product-induced apoptosis and endoplasmic reticulum stress in vascular smooth muscle cells

“…Fluorescence micrographs were all analyzed using a custom-built macro in the ImageJ software 11 . Briefly, the background was removed with a rolling ball radius of 1000 pixels and white noise was subtracted after measuring the grey value distribution of an area that doesn't contain any fluorescence.…”

“…Here we use an AGE preparation strictly composed of CML-HSA, which has been shown to be more potent at activating RAGE than glucose-incubated HSA 11 . Moreover, degree of CML modifications in our product is very high as determined using TNBSA assays.…”

“…We previously showed that RAGE activation of vascular smooth muscle cells (VSMC) by AGE inhibits the expression of their functional contractile phenotype 11 . Therefore, by affecting VSMC functions, including signal transduction, cell contraction and cytoskeletal organization, RAGE signaling is suspected to contribute to hypertension and vascular dysfunction frequently observed in diabetic subjects.…”

Serum levels of advanced glycation end products in type II diabetic patients with acute cerebral infarction

“…Under pathological conditions, cellular interactions with AGEs induce biologic responses that have been linked directly to the development of diabetic vascular complications. Via interacting with AGEs (RAGE) receptor, AGEs are demonstrated to be involved in the generation of oxidative stress in various types of cells and subsequently triggering vascular inflammation [7,8], promoting the proliferation of vascular smooth muscle cells [9,10], potentiating adhesion, aggregation and activation of leukocyte [11], accelerating platelet aggregation and fibronectin formation, elevating macrophage infiltration [12], leading to the occurrence of lipid metabolic disorder, thus facilitating atherosclerosis [13,14]. However, the exact role of AGEs in the pathogenesis of cerebral thrombosis remains poorly understood.…”