Abstract
Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of thoracic aortic aneurysms (TAAs). Cytokines [Interleukin (IL)-Iβ, IL-2, IL-6, and TNF-α)] increase the expression of MMP-2 and -3. Advanced glycation end products (AGEs) interact with cell receptors to increase the release of cytokines. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, thus contributing to the formation of TAAs. The study population was composed of 17 control subjects and 20 patients with TAA. Blood samples were collected for measurement of serum sRAGE, esRAGE, AGEs, cytokines, and MMPs. AGEs, sRAGE, and esRAGE were measured using ELISA kits, whereas the remaining parameters were measured using the Luminex Multi-Analyte system. The levels of sRAGE were lower, while the levels of AGEs, AGEs/sRAGE, AGEs/esRAGE, cytokines and MMPs were higher in patients with TAA compared to controls. The levels of sRAGE were inversely correlated with cytokines and MMPs, while AGEs, AGEs/sRAGE and AGEs/esRAGE were positively correlated with cytokines and MMPs. Cytokines were positively correlated with MMPs. The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE are risk factors for TAA.
Highlights
The mechanism of development of thoracic aortic aneurysms (TAAs) is complex
It is hypothesized that low levels of serum soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) and high levels of aorta.scienceinternational.orgAdvanced glycation end products (AGEs), AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels Matrix metalloproteinases (MMPs), contributing to the formation of TAAs
The data show that serum levels of sRAGE are lower, and the levels of AGEs, AGEs/sRAGE, and AGEs/ esRAGE are higher, in patients with TAA compared to control subjects
Summary
The mechanism of development of thoracic aortic aneurysms (TAAs) is complex. The characteristic features of TAAs are destruction of collagen and elastin in media and adventitia, loss of smooth muscle cells with thinning of aortic wall, and transmural infiltrationAccessible online at: http://aorta.scienceinternational.orgAdvanced glycation end products (AGEs) are a heterogeneous group of irreversible aducts resulting from nonenzymatic glycation and oxidation of proteins, nucleic acids and lipids [7, 8]. There are two isoforms of c-truncated RAGE: total soluble RAGE (sRAGE) [12] and endogenous secretory RAGE (esRAGE) [13] Both sRAGE and esRAGE act as a decoy for RAGE ligands and compete with membrane-bound RAGE for ligand binding [14], reducing the production of cytokines [3,4,5,6] and ROS [15]. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, contributing to the formation of TAAs. Methods: The study population was composed of 17 control subjects and 20 patients with TAA. Conclusions: The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/ sRAGE, and AGEs/esRAGE are risk factors for TAA
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